(P 08) PRELIMINARY CLINICAL ACTIVITY OF THE TYPE II RAF INHIBITOR TOVORAFENIB IN RAF FUSION-DRIVEN RECURRENT/PROGRESSIVE SARCOMAS

Objective: BRAF and CRAF/RAF1 (known collectively as “RAF”) fusions are rare oncogenic alterations in sarcoma. Tovorafenib is an investigational, oral, selective, CNS-penetrant, type II RAF inhibitor with clinical activity in BRAF-fusion pediatric low-grade glioma (pLGG) and adult melanoma.

Early clinical activity of tovorafenib monotherapy in two adolescent and young adult (AYA) patients─one with an inoperable, locally advanced BRAF-fusion inflammatory myofibroblastic tumor (IMT) and another with a CRAF-fusion spindle cell sarcoma─ as of 26 May 2023 is reported.

Methods: Two ongoing phase 2 studies are evaluating tovorafenib monotherapy: FIREFLY-1 (FF-1) (PNOC026; NCT04775485), in pediatric patients (6 months to 25 years of age) with recurrent/progressive RAF-fusion advanced solid tumors in arm 3, and sub-study DAY101-102a of FIRELIGHT-1 (FL-1) (NCT04985604), in patients ≥12 years of age with RAF-fusion or CRAF/RAF1-amplified solid tumors. In both trials, tovorafenib 420 mg/m2 (maximum 600 mg) is administered PO once weekly in 28-day cycles until disease progression and the primary endpoint in solid tumors is overall response rate per RECIST version 1.1.

Results: Patient 1 is a 15-year-old female with a locally advanced pelvic IMT harboring an ETV6-BRAF fusion. Surgical resection of the large tumor was contraindicated due to high morbidity risk. She enrolled in Arm 3 of FF-1 and treatment was initiated at 600 mg once weekly.

After 2 cycles of treatment, a 16% reduction (investigator-assessed) in the target lesion was reported and the tumor was deemed operable. Treatment continued for 3 more weeks (2.5 cycles total), and the tumor was resected with R0 margins. As the risk of relapse was low, tovorafenib was discontinued post-surgery. No significant surgically-related morbidities were reported.

TRAEs included G2 myalgia, fatigue, and headache that resolved following a reduction in tovorafenib dose to 500 mg. Transient G1/2 maculopapular rash and G2 acneiform rash were observed and resolved with supportive care medications and the dose reduction. The patient also experienced G1 anorexia, anemia, periorbital and localized edema, skin discoloration, chest erythema, pyrexia, nausea, and vomiting.

Patient 2 is a 30-year-old Asian female enrolled in FL-1 with metastatic undifferentiated spindle cell sarcoma harboring an APPL2-RAF1 fusion previously treated with radiation, multiple surgical resections, and 2 lines of systemic therapy (cisplatin + etoposide [best response of stable disease] followed by docetaxel + gemcitabine [best response of partial response {PR} but progressed after 6 cycles]). A PR was reported after 2 cycles of tovorafenib (SPPD decrease of 47% from baseline [BL] on CT imaging), with a deepening of response with continued treatment of 10 cycles at data cut off (SPPD decrease of 72% from BL on CT imaging).

TRAEs included G1 acne, pruritus, and hypothyroidism, and G3 CPK elevation. A G3 left retinal hemorrhage occurred with a concomitant eye trauma on C2D27 which resolved after 5 weeks. Tovorafenib dose was interrupted and then reduced to 500 mg with no further recurrences.

Conclusion: Tovorafenib has clinical activity and a manageable safety profile in these two AYA patients with RAF fusion sarcoma. These reports provide additional evidence of the antitumor activity of tovorafenib in RAF fusion-driven tumors beyond pLGG Early tumor shrinkage minimizing potential morbidities facilitated curative tumor resection in one patient where surgical intervention was not previously possible and a continued rapid, durable tumor response in another. Genomic analysis of all sarcomas is warranted to identify rare oncogenic gene fusions, especially when such alterations are targetable. Both the FF-1 and FL-1 trials are ongoing and continue to enroll.