Tovorafenib (DAY101)

No efficacy or safety results for tovorafenib as first-line therapy had been reported as of September 2026. The only first-line trial, LOGGIC/FIREFLY-2 (NCT05566795), is a randomized (1:1), open-label, phase 3 trial comparing tovorafenib once weekly with investigator's choice of 4 standard-of-care chemotherapy regimens (COG vincristine/carboplatin, SIOPe-LGG vincristine/carboplatin, vinblastine, or monthly carboplatin) in participants aged 6 months to 25 years with RAF-altered pLGG requiring first-line systemic therapy. Participants with NF1 or with additional activating molecular alterations are excluded, randomization is stratified by tumor location, fusion versus mutation, CDKN2A status, and infant chiasmatic-hypothalamic glioma, and participants who progress on chemotherapy may cross over to tovorafenib. Tovorafenib is given at 420 mg/m2 (maximum 600 mg), which is higher than the approved 380 mg/m2. Enrollment reached 169 randomized participants at 110 sites by 15 January 2025 and was completed in May 2026 with approximately 400 participants at approximately 140 sites. The primary analysis is expected approximately 12 months after the last enrollment, with topline data expected by mid-2027; the FDA postmarketing requirement specifies an interim report in April 2028 and a final report in April 2032. The sources differ on the primary endpoint: the 2024 design publication specifies IRC-assessed ORR per RANO-LGG, whereas the registry record (which counts minor responses as responses) and the May 2026 sponsor announcement describe ORR per RAPNO-LGG, and the EMA reports that the protocol was amended to RAPNO-LGG after 113 of 400 participants had been recruited. The design assumed a 30% ORR with chemotherapy and provides approximately 85% power to detect a 15% ORR improvement and a PFS hazard ratio of 0.67 (assumed median PFS 4.5 versus 3 years). Key secondary endpoints include PFS, EFS, TTNT, overall survival, and patient-reported outcomes.

All available efficacy data concern relapsed or refractory disease. The single-arm phase 2 FIREFLY-1 trial enrolled 137 participants (77 in the registrational arm 1 and 60 in expansion arm 2) with a median of 3 prior systemic therapies; 83 of 137 (61%) had received MAPK pathway-targeted therapy. At the 5 June 2023 data cutoff, IRC-assessed ORR in arm 1 was 67% by RANO-HGG (69 evaluable participants; the protocol primary endpoint), 51.3% by RAPNO-LGG, and 52.6% by RANO-LGG (76 evaluable participants each), with a median DOR of 13.8 months and median PFS of 13.8 months by RAPNO-LGG; the FDA based accelerated approval on RAPNO-LGG ORR and DOR. At the 10 May 2024 cutoff, RAPNO-LGG ORR was 52.6% with a median DOR of 18.0 months, and RANO-HGG ORR was 71.0% by IRC versus 49.3% by investigators. At the 3-year analysis (6 June 2025; median study duration 40.6 months), RAPNO-LGG ORR was 40 of 76 (53%), median DOR was 19.4 months (24.0 months in MAPK inhibitor-naive and 16.6 months in previously treated participants), median PFS was 16.6 months, 24-month PFS was 32%, and median TTNT was 42.6 months; 38 participants (50%) continued treatment beyond RAPNO-defined progression. Of 39 participants who entered the post-treatment observation period, 30 (77%) were treatment free for at least 12 months and 12 (31%) met criteria for rebound tumor growth, including 4 of 6 with BRAF V600E; 8 were retreated, with a median tumor size change of -38%. Among 35 participants with optic pathway glioma and at least 2 visual acuity assessments, visual acuity was preserved in 80% and improved in 31%. PedsQL Cancer Module scores generally remained stable or improved during the first year, with respondents declining from 51 at baseline to 32 at cycle 13. In the phase 1 PNOC014 study (44 participants aged 1 to 25 years with recurrent or progressive MAPK-altered tumors), 25 of 27 centrally reviewed participants (93%) had complete response, partial response, or stable disease, and 420 mg/m2 was selected as the recommended phase 2 dose.

All safety data also derive from relapsed or refractory populations. The US label has no contraindications and no boxed warning, and no REMS is required. In the pooled label safety population, hemorrhage occurred in 37% (intratumoral hemorrhage 9%; 1 grade 5 tumor hemorrhage), rash in 67% (grade 3 in 12%), photosensitivity in 12%, and increased AST and ALT in 74% and 42%; effects on growth occurred in 46% of 133 FIREFLY-1 participants aged 18 years or younger (35% grade 3 or higher). In FIREFLY-1, the most common adverse reactions were rash (77%), hair color changes (76%), fatigue (55%), viral infection (55%), and vomiting (50%); serious adverse reactions occurred in 45%, and adverse reactions led to dose interruption in 57%, dose reduction in 24%, and permanent discontinuation in 7%. At the 3-year analysis (137 participants), grade 3 or higher TEAEs occurred in 113 (82%) and serious TEAEs in 77 (56%); TRAEs led to discontinuation in 18 (13%) and dose reduction in 45 (33%); decreased growth velocity was reported in 61 (45%; grade 3 or higher in 46, 34%) and intratumoral hemorrhage in 21 (15%); and 5 participants (4%) had grade 5 TEAEs assessed as not related to tovorafenib. Median annualized growth velocity increased from 1.40 cm/year during treatment to 7.23 cm/year after treatment; 67 of 74 participants (91%) with on-treatment growth reduction had growth recovery and 53 (72%) had catch-up growth, and no premature growth plate fusions were observed. In PNOC014, 11 of 12 participants (92%) treated for more than 6 months who were not postpubertal had grade 3 growth suppression. No ocular toxicity, adverse impact on cardiac function, or abnormal weight gain was observed in FIREFLY-1. The EU risk management plan lists growth retardation and intratumoral hemorrhage as important identified risks, decreased fertility as an important potential risk, and long-term safety as missing information.