Plexxikon is conducting a clinical study to learn how PLX9486 may affect cancer cells with certain mutations in the KIT gene, specifically in patients with advanced solid tumors including GIST. By blocking certain KIT gene mutations, PLX9486 may kill the cancer cells with the mutation and/or stop the tumor from growing. By combining PLX9486 and other KIT inhibitors, including pexidartinib and Sunitinib, the investigators hope to block most gene mutations in KIT.

Preclinical data indicate that pexidartinib is designed to hit KIT Exons 13 and 14 quite well; whereas PX9486 hits Exons 17 and 18. By combining the two, it is hoped that more of the secondary mutations will be more efficiently inhibited.

At CTOS’s November, 2017 conference, Plexxikon presented a poster on its Phase 1 PLX9486 study. The poster reflects the preliminary results of the trials which is being conducted nationwide by leading and well-known GIST experts.  See the poster here.

According to the poster, “Background: In GIST, activating mutations in KIT exon 9 or 11 occur in 80% of patients. Tyrosine kinase inhibitors (TKIs) such as Imatinib, Sunitinib and Regorafenib have markedly improved treatment of GIST. However, most GIST patients develop resistance mutations in exon (ex) 13, 14, 17 or 18. PLX9486 is a novel TKI with activity against primary KIT mutations (ex 9 and 11) and against activation loop mutations (ex 17 and 18).”

The conclusions drawn from this Phase I Study were presented:

  • PLX9486 as a single agent selectively inhibits a spectrum of KIT mutations including difficult-to-treat exon 17/18 activation loop variants.
  • 500 mgQD was established as the Recommended Phase 2 Dose (Maximum Tolerated Dose not reached); predicted efficacious exposure achieved; well tolerated
  • Interim results in heavily pretreated GIST patients (100% in three or more prior regimens) @ doses equal to or greater than 500 mg daily: 1 partial response; CBR of 57%; median progression-free survival of 5 months.
  • Combination regimen (PLX9486+pexidartinib) selectively inhibits all common primary and secondary KIT mutations
  • Combination RP2Dlikely 500 mg PLX9486 +600 mg PLX3397 daily with food; combination MTD not reached; predicted efficacious exposure achieved; clinical benefit demonstrated in patients who progressed on multiple TKIs; well tolerated
  • Sunitinib combination in planning
  • Further accrual in earlier line patients is planned

For additional details on this Phase I study, please refer to the details of the poster that Plexxikon provided. For a list of clinical trial sites participating in the study, please see: here