LOXO-292: Investigating RET Alterations

LOXO-292 clinical trial

LOXO-292 is currently being evaluated in an open-label, multicenter, global phase 1 trial in adolescent and adult patients with advanced solid tumors harboring a RET fusion or a RET point mutation.1

The trial includes 2 phases: dose escalation and dose expansion. In the expansion phase, 5 cohorts are planned to allow for the characterization of preliminary activity of LOXO-292 in different genetically defined populations1:

  1. Patients with RET fusion lung cancer who have had any number of prior RET inhibitor treatments
  2. Patients with RET fusion lung cancer who have had no prior RET inhibitor treatments
  3. Patients with RET-mutant medullary thyroid carcinoma who have had any number of prior RET inhibitor treatments
  4. Patients with RET-mutant medullary thyroid carcinoma who have had no prior RET inhibitor treatments
  5. Patients with other RET-altered or RET-dependent solid tumors

Study Design1

LOXO-292 clinical trial study design diagram. a Bona fide RET fusion, ATA moderate- and high-risk RET mutation.

Alterations in the RET receptor tyrosine kinase, including gene fusions and activating point mutations, represent oncogenic drivers that occur across multiple tumor types.2-9

RET fusions have been identified in:

  • ≈10%-20% of papillary thyroid carcinomas10-15
  • ≈2% of non—small cell lung cancer (NSCLC)3-6,8
  • A subset of colon and other cancers2,7-9

RET fusions can occur with a variety of fusion partners, with the most common being KIF5B and CCDC6 in NSCLC and CCDC6 and NCOA4 in papillary thyroid carcinoma.16-19

Additionally, RET point mutations account for approximately 60% of medullary thyroid carcinoma20-26

Simple diagram of human body indicating the types and locations of tumors that may harbor a RET fusion or RET point mutation, including non-small cell lung cancer, thyroid cancer, colon cancer, and other solid tumors. Conditions under investigation
  • bullet Medullary thyroid carcinoma
    Papillary thyroid carcinoma
  • bullet Non—small cell lung cancer
  • bullet Other solid tumors

RET-mutated cancers are uniquely dependent on this singular, constitutively activated pathway.3-6 This “oncogene addiction” provides strong justification for a highly focused therapy, and RET alterations across various cancer types represent a set of highly actionable targets that, to date, have not been adequately addressed by existing multitargeted tyrosine kinase inhibitors.16,27,28

LOXO-292, an investigational agent, is a highly selective and potent RET inhibitor in preclinical models.29 A clinical trial is currently under way to examine the potential activity of LOXO-292 against the range of RET alterations found in human cancers, including activating point mutations, gene fusions, and anticipated acquired resistance mechanisms.1

The inhibitory activity of LOXO-292 is independent of the RET fusion partner or RET mutation. LOXO-292 is also highly selective for the RET kinase.29,30 LOXO-292 is currently being evaluated in patients to determine if this inhibitory activity and selectivity translates into deep, sustained RET inhibition, without significant off-target toxicity.1 Importantly, LOXO-292 has demonstrated preliminary antitumor activity in patients, both systemically as well as in the brain.31

Select inclusion criteria1

  1. ≥12 years of age with a locally advanced or metastatic solid tumor that has progressed following or has not adequately responded to standard therapy
  2. Any number of prior TKIs with anti-RET activity
  3. Evidence of a RET gene alteration in tumor and/or blood, identified through molecular assays performed in a CLIA, ISO/IEC, CAP, or similarly certified lab; a RET gene alteration is not initially required during dose escalation
  4. ECOG 0, 1, or 2; life expectancy ≥3 months; and adequate hematologic, hepatic, and renal function

Select exclusion criteria1

  1. Prior therapies
    • No investigational agent or anticancer therapy within five half-lives or 2 weeks (whichever is shorter) prior to planned start of LOXO-292
    • Radiotherapy must be completed at least 1 week prior to planned start of LOXO-292 (4 weeks if wide field or >30% of bone marrow)
    • No unresolved toxicities higher than CTCAE grade 1 (except alopecia and grade 2 neuropathy from prior platinum therapy)
  2. Patients with primary CNS tumors or CNS metastases must be neurologically stable
  3. Clinically significant active cardiovascular disease or prolonged corrected QT interval (QTc)
  4. Uncontrolled infection
  5. Current treatment with certain CYP3A4 inhibitors or inducers
  6. Pregnancy or lactation

For more information about the LOXO-292 clinical trial, please refer to the Loxo Oncology RET program or visit clinicaltrials.gov (NCT03157128). Interested physicians and patients may contact the Loxo Oncology RET Physician and Patient Clinical Trial Hotline at 1-855-RET-4-292 or e-mail clinicaltrials@loxooncology.com.

loxooncology.com

References
  1. Drilon AE, Bauer TM, Subbiah V, et al. A phase 1 study of oral LOXO-292 in patients with advanced solid tumors, including RET-fusion non-small cell lung cancer, medullary thyroid cancer and other tumors with increased RET activity. Poster presented at: European Society for Medical Oncology 2017 Congress; September 8-12, 2017; Madrid, Spain.
  2. Ballerini P,Struski S, Cresson C, et al. RET fusion genes are associated with chronic myelomonocytic leukemia and enhance monocytic differentiation. Leukemia. 2012;26(11):2384-2389.
  3. Ju YS, Lee W-C, Shin J-Y, et al. A transforming KIF5B and RET gene fusion in lung adenocarcinoma revealed from whole-genome and transcription sequencing. Genome Res. 2012;22(3):436-445.
  4. Kohno T, Ichikawa H, Totoki Y, et al. KIF5B-RET fusions in lung adenocarcinoma. Nat Med. 2012;18(3):375-377.
  5. Lipson D, Capelletti M, Yelensky R, et al. Identification of new ALK and RET gene fusions from colorectal and lung cancer biopsies. Nat Med. 2012;18(3):382-384.
  6. Takeuchi K, Soda M, Togashi Y, et al. RET, ROS1 and ALK fusions in lung cancer. Nat Med. 2012;18(3):378-381.
  7. Bossi D, Carlomagno F, Pallavicini I, et al. Functional characterization of a novel FGFR1OP-RET rearrangement in hematopoietic malignancies. Mol Oncol. 2014;8(2):221-231.
  8. Stransky N, Cerami E, Schalm S, Kim JL, Lengauer C. The landscape of kinase fusions in cancer. Nat Commun. 2014;5:4846.
  9. Yoshihara K, Wang Q, Torres-Garcia W, et al. The landscape and therapeutic relevance of cancer-associated transcript fusions. Oncogene. 2015;34(37):4845-4854.
  10. Fusco A, Grieco M, Santoro M, et al. A new oncogene in human thyroid papillary carcinomas and their lymph-nodal metastases. Nature. 1987;328(6126):170-172.
  11. Ito T, Seyama T, Iwamoto KS, et al. Activated RET oncogene in thyroid cancers of children from areas contaminated by Chernobyl accident. Lancet. 1994;344(8917):259.
  12. Fugazzola L, Pilotti S, Pinchera A, et al. Oncogenic rearrangements of the RET proto-oncogene in papillary thyroid carcinomas from children exposed to the Chernobyl nuclear accident. Cancer Res. 1995;55(23):5617-5620.
  13. Bounacer A, Wicker R, Caillou B, et al. High prevalence of activating ret proto-oncogene rearrangements, in thyroid tumors from patients who had received external radiation. Oncogene. 1997;15(11):1263-1273.
  14. Prescott JD, Zeiger MA. The RET oncogene in papillary thyroid carcinoma. Cancer. 2015 Jul 1;121(13):2137-2146.
  15. Cancer Genome Atlas Research Network. Integrated genomic characterization of papillary thyroid carcinoma. Cell. 2014;59(3):676-690.
  16. Kohno T, Nakaoku T, Tsuta K, et al. Beyond ALK-RET, ROS1 and other oncogene fusions in lung cancer. Transl Lung Cancer Res. 2015;4(2):156-164.
  17. Lee MS, Kim RN, I H, et al. Identification of a novel partner gene, KIAA1217, fused to RET: functional characterization and inhibitor sensitivity of two isoforms in lung adenocarcinoma. Oncotarget. 2016;7(24):36101-36114.
  18. Velcheti V, Thawani R, Khunger M, et al. FRMD4A/RET: a novel RET oncogenic fusion variant in non-small cell lung carcinoma. J Thorac Oncol. 2017;12(2):e15-e16.
  19. Santoro M, Carlomagno F. Central role of RET in thyroid cancer. Cold Spring Harb Perspect Biol. 2013;5(12):a009233. doi:10.1101/cshperspect.a009233
  20. Donis-Keller H, Dou S, Chi D, et al. Mutations in the RET proto-oncogene are associated with MEN 2A and FMTC. Hum Mol Genet. 1993;2(7):851-856.
  21. Mulligan LM, Kwok JB, Healey CS, et al. Germ-line mutations of the RET proto-oncogene in multiple endocrine neoplasia type 2A. Nature. 1993;363(6428):458-460.
  22. Carlson KM, Dou S, Chi D, et al. Single missense mutation in the tyrosine kinase catalytic domain of the RET protooncogene is associated with multiple endocrine neoplasia type 2B. Proc Natl Acad Sci U S A. 1994;91(4):1579-1583.
  23. Eng C, Smith DP, Mulligan LM, et al. Point mutation within the tyrosine kinase domain of the RET proto-oncogene in multiple endocrine neoplasia type 2B and related sporadic tumours. Hum Mol Genet. 1994;3(2):237-241.
  24. Hofstra RM, Landsvater RM, Ceccherini I, et al. A mutation in the RET proto-oncogene associated with multiple endocrine neoplasia type 2B and sporadic medullary thyroid carcinoma. Nature. 1994;367(6461):375-376.
  25. Agrawal N, Jiao Y, Sausen M, et al. Exomic sequencing of medullary thyroid cancer reveals dominant and mutually exclusive oncogenic mutations in RET and RAS. J Clin Endocrinol Metab. 2013;98(2):E364-E369.
  26. Ji JH, Oh YL, Hong M, et al. Identification of driving ALK fusion genes and genomic landscape of medullary thyroid cancer. PLoS Genet. 2015;11(8):e1005467.
  27. Plaza-Menacho I, Mologni L, McDonald NQ. Mechanisms of RET signaling in cancer: current and future implications for targeted therapy. Cell Signal. 2014;26(8):1743-1752.
  28. Gautschi O, Milia J, Filleron T, et al. Targeting RET in patients with RET-rearranged lung cancers: results from the global, multicenter RET registry. J Clin Oncol. 2017;35(13):1403-1410.
  29. Brandhuber B, Haas J, Tuch B, et al. The development of LOXO-292, a potent, KDR/VEGFR2-sparing RET kinase inhibitor for treating patients with RET-dependent cancers. Poster presented at: European Organisation for Research and Treatment of Cancer-National Cancer Institute-American Association for Cancer Research Symposium; November 29-December 2, 2016; Munich, Germany.
  30. Data on file. Loxo Oncology, Inc.
  31. Velcheti V, Bauer T, Subbiah V, et al. LOXO-292, a potent, highly selective RET inhibitor, in MKI-resistant RET fusion-positive lung cancer patients with and without brain metastases. Proceedings from: International Association for the Study of Lung Cancer 18th World Conference on Lung Cancer; October 15-18, 2017; Yokohama, Japan. Abstract OA 12.07.