Summary: benchmarks for first-line therapy outcomes

Overall survival in pLGG is high regardless of first-line therapy (5-year overall survival 86% in COG A9952, 89% in SIOP-LGG 2004, and 94.4% with vinblastine), so expected benefits of new first-line therapy are measured by response, durability of disease control, and functional outcomes. Chemotherapy benchmarks are 5-year EFS of 39% (carboplatin plus vincristine, COG), 5-year PFS of 46% (vincristine plus carboplatin, SIOP), and 5-year PFS of 53.2% (vinblastine). In the only completed randomized first-line comparison of a targeted therapy (110 participants with BRAF V600 pLGG), dabrafenib plus trametinib produced an ORR of 47% versus 11% and a median PFS of 20.1 versus 7.4 months with carboplatin plus vincristine.

FIREFLY-2 was powered (approximately 400 participants, 85% power) to detect a 15% absolute improvement in ORR over an assumed 30% control-arm ORR, and a PFS hazard ratio of 0.67 based on an assumed median PFS of 4.5 years with tovorafenib versus 3 years with chemotherapy. In the relapsed or refractory setting (FIREFLY-1, 76 participants), tovorafenib produced an ORR of 51% by RAPNO criteria with a median duration of response of 13.8 months; among 35 participants with optic pathway glioma and at least 2 visual acuity assessments, visual acuity was preserved in 80% and improved in 31%. Visual acuity improved in 20% of participants with optic pathway glioma treated with first-line vinblastine and in 4 of 19 participants (21%) with recurrent optic pathway and hypothalamic glioma treated with selumetinib. In May 2026 the sponsor described the FIREFLY-2 primary endpoint as ORR based on RAPNO-LGG criteria, whereas the 2024 design publication specified RANO-LGG.

LOGGIC/FIREFLY-2: assumed outcomes underlying the sample size

“To assess the ORR per the primary endpoint, the planned sample size of approximately 400 patients will provide around 85% power to detect a 15% improvement for the tovorafenib arm at a two-tailed level of significance of 0.05, assuming a 30% ORR in the control arm and a dropout rate of up to 10%. To assess PFS as per the key secondary endpoint, the planned sample size of approximately 400 patients will provide around 85% power to detect a hazard ratio of 0.67 for PFS at a two-tailed level of significance of 0.05, assuming the median PFS for the tovorafenib arm is 4.5 years versus a median of three years for the control arm.” (opens the source at this quote in a new tab)

LOGGIC/FIREFLY-2: endpoints as described at completion of enrollment

“The primary endpoint of the trial is overall response rate (ORR), including duration of response (DOR), based upon Response Assessment in Pediatric Neuro-Oncology Low-Grade Glioma (RAPNO-LGG) criteria, with key secondary endpoints including progression-free survival (PFS) and event-free survival (EFS) per RAPNO-LGG, time to next treatment (TTNT), overall survival (OS) and other measures, including patient-reported outcomes.” (opens the source at this quote in a new tab)

Functional outcomes assessed in LOGGIC/FIREFLY-2

“Importantly, this study also includes endpoints to evaluate improvements in neurologic outcomes, visual function in patients with optic pathway glioma (OPG), and patient-reported outcomes to better describe the overall impact on patients’ lives and activities of daily living.” (opens the source at this quote in a new tab)

Benchmark outcomes with first-line targeted therapy: dabrafenib plus trametinib

“Clinical benefit was observed in 86% of the patients receiving dabrafenib plus trametinib and in 46% receiving chemotherapy (risk ratio, 1.88; 95% CI, 1.3 to 2.7).” (opens the source at this quote in a new tab)

“Duration of response (DOR) was 23.7 months (95% CI: 14.5, NE) in the D+T arm and not estimable (95% CI: 6.6, NE) in the C+V arm.” (opens the source at this quote in a new tab)

Benchmark outcomes with tovorafenib in relapsed or refractory pLGG

“In an efficacy population of 76 patients, the ORR was 51% (95% confidence interval (CI): 40, 63), and the median DoR was 13.8 months (95% CI: 11.3, not estimable).” (opens the source at this quote in a new tab)

Visual outcomes with systemic therapy for optic pathway glioma

“VA per patient was preserved for 80% of patients; 31% demonstrated improved VA; VA per eye was preserved in 87%, with 27% improving.” (opens the source at this quote in a new tab)

“Visual improvement was observed in 20% of patients with optic pathway glioma.” (opens the source at this quote in a new tab)

“Nineteen of 25 patients were evaluable for visual acuity which improved in 4/19 patients (21%), was stable in 13/19 (68%), and worsened in 2/19 (11%).” (opens the source at this quote in a new tab)

Goals of therapy in a chronic disease

“pLGG is now conceptualized as a chronic disease, underscoring the importance of functional outcomes and quality-of-life measures.” (opens the source at this quote in a new tab)

“The current focus of our efforts to improve outcomes in pLGG is to identify agents that lead to a durable response and reduce morbidity.” (opens the source at this quote in a new tab)

Visual acuity change during first-line dabrafenib plus trametinib versus carboplatin and vincristine

“The change from baseline in visual acuity was assessed in patients with tumors located near the optic chiasm (25 with dabrafenib plus trametinib and 11 with chemotherapy)” (opens the source at this quote in a new tab)
“Although visual acuity remained stable in most patients in the two groups, visual acuity per eye was improved in more patients who received dabrafenib plus trametinib than in those who received chemotherapy (14 of 41 eyes examined [34%] vs. 2 of 18 eyes examined [11%]).” (opens the source at this quote in a new tab)

Landmark progression-free survival at 6 and 12 months with first-line dabrafenib plus trametinib versus chemotherapy

“At 6 months, the estimated progression-free survival was 87% (95% CI, 77 to 93) with dabrafenib plus trametinib and 58% (95% CI, 39 to 73) with chemotherapy; the percentages at 12 months were 67% (95% CI, 53 to 77) and 26% (95% CI, 10 to 46), respectively.” (opens the source at this quote in a new tab)

Discordance between imaging response and visual outcome in optic pathway glioma

“There was poor correlation between imaging and VA outcomes (n=66). Twenty-two per cent of patients with improved imaging outcomes had improved VA, whereas 30% of patients experienced worse VA despite improved or stable imaging outcomes” (opens the source at this quote in a new tab)
“There is however increasing evidence that serial changes in VA do not reliably detect tumour progression and, conversely, tumour progression does not reliably correlate with decreased VA.” (opens the source at this quote in a new tab)

Outcome measures prioritized by clinicians and survivors

“The relevance of outcome measures after childhood cancer was recently investigated among 87 clinicians via two step Delphi questionnaire rounds and online focus groups of survivors” (opens the source at this quote in a new tab)
“For pediatric LGG, the fields of interest in late outcome were defined as motor function, vision, hypothalamic function, physical aspects, subsequent neoplasm, and psychosocial and neurocognitive aspects of quality of life besides overall survival and cause-specific mortality.” (opens the source at this quote in a new tab)

Treatment continued to loss of clinical benefit versus a fixed number of chemotherapy cycles

“Treatment was continued until loss of clinical benefit (as determined by the investigator), development of unacceptable toxic effects, initiation of a new anticancer therapy, completion of the protocol-defined number of cycles (in the chemotherapy group), loss to follow-up, or death.” (opens the source at this quote in a new tab)
“Continuation of dabrafenib plus trametinib after investigator-determined disease progression was allowed if there was an expectation of continued clinical benefit.” (opens the source at this quote in a new tab)
“Future studies are needed to evaluate functional outcomes (e.g., visual acuity), further molecular characterization, and most effective treatment duration.” (opens the source at this quote in a new tab)

Vision during first-line vinblastine

“It is noteworthy that in this study, only 4 out of all evaluable patients for visual response (24 patients) experienced worsening of vision during treatment.” (opens the source at this quote in a new tab)

Visual acuity preserved or improved in most children after first-line chemotherapy for optic pathway glioma

“With an average follow-up of 6.5 years, VA improved or remained stable in 59% and 61% of children with NF1 and sporadic OPGs, respectively.” (opens the source at this quote in a new tab)
“Although visual outcomes after chemotherapy are not optimal, timely treatment arrested the decline in VA in most children, and some children regained vision.” (opens the source at this quote in a new tab)

Tovorafenib (DAY101)

Expected outcomes of therapy