(P 267) THE RAF/MEK INHIBITOR VS-6766 SHOWS EFFICACY IN RAS-MUTANT PEDIATRIC PRECLINICAL XENOGRAFT MODELS- A REPORT FROM THE PEDIATRIC PRECLINICAL IN VIVO TESTING CONSORTIUM

Objective: VS-6766 is an allosteric MEK inhibitor that dually inhibits MEK and RAF. VS-6766 has shown benefit in tumors with mutant RAS and clinical trials are underway in adult cancers; however, activity in pediatric cancer has not been defined. Pediatric histologies such as acute leukemias (ALL) and rhabdomyosarcoma (RMS) have an appreciable frequency of RAS mutations. To evaluate the role of RAF/MEK inhibition in pediatric cancers, VS-6766 was tested against pediatric solid tumor and leukemia patient-derived xenografts (PDXs).

Methods: VS-6766 was provided by Verastem Oncology and given orally at 0.3 mg/kg daily. Tolerability testing was performed in 3 non-tumor bearing immunodeficient mice at 100%, 71%, 33%, and 24% of the recommended dose. To test efficacy, PDXs were dosed with VS-6766 and compared to control (see Table). To evaluate drug combinations, RMS PDXs were treated with VS-6766 in doublet with 14 other drugs targeting additional areas of the MAPK/ERK pathway along with untreated control, VS-6766 alone, and vincristine + irinotecan (standard of care) for a total of 17 treatment groups. Models were labeled with luciferase for weekly bioluminescent monitoring of tumor burden along with calipers.

Results: VS-6766 was well tolerated in mice. In ALL, 5/27 evaluable models achieved objective responses with 4/5 responders harboring a RAS mutation (2 KRAS, 2 NRAS). In MPNST, 3/4 models had stable disease with 2 of those harboring NF-1 mutations. In RMS, survival advantage was noted in 4/5 models tested for 4 weeks, and 7/9 models tested for 16 weeks. All 11 RMS responders had RAS mutations (4 HRAS, 2 KRAS, 5 NRAS). Of the 3 non-responder PDXs, 1 had HRAS and 2 were non-mutated. In combination testing, survival advantage was most notable when VS-6766 was combined with VS-4718 (FAK), everolimus (mTOR), copanlisib (PI3Kδ/α), capivasertib (AKT), BBP-398 (SHP2) and LY3023414 (PI3K) compared to VS-6766 alone.

Conclusion: VS-6766 exhibited antitumor activity across several pediatric cancers. As single agent, there was activity in the majority of solid tumor models tested with prolongation of time on study and stabilization of disease. Solid tumor models harboring RAS mutations appear more likely to respond, although limited non-mutant models were tested. The response of VS-6766 in RMS was further enhanced when used in combination, and additional studies are needed across a broader panel of pediatric PDXs to prioritize the best combination for clinical development.

Preclinical Testing Details. SMT, single mouse trial (1 mouse/treatment group); Con, conventional (6 mice/group); Twin Mouse (2 mice/group)