Discussion
tumor, seizures, bone marrow failure, Intratumoral hemorrhage, cancer, rash, hemorrhage, heterogenous, fatigue, hypothalamic/chiasmatic gliomas, anemia, pruritus, paronychia, heterogeneous disease, endocrine abnormalities, TRAEs, leptomeningeal disease, intratumoral hemorrhage, PD, tumor hemorrhage, deaths, tumors, dermatitis
TUMOR, BONE MARROW FAILURE, ENDOCRINE DISORDER, CANCER, DISEASE, BLEEDS, ANEMIA, HEMORRHAGE, SECONDARY, PARONYCHIA, TUMORS, DERMATITIS
In this international, multicenter, single-arm phase 2 trial, tovorafenib monotherapy resulted in clinically meaningful, rapid and durable tumor responses in children and young adults with This trial was designed with IRC-assessed ORR as the primary endpoint, evaluated according to RANO-HGG criteria. These criteria assess tumor response based primarily on T1-weighted, contrast-enhanced imaging. At the time the original protocol was initiated, the largest trial in pLGG with published efficacy results in the relapsed/refractory population primarily used T1-weighted, contrast enhancement–based, centrally reviewed assessment criteria to evaluate the treatment effect of vinblastineFor patients with pLGG, decrease in contrast-enhancing tumor may not represent all aspects of anti-tumor activity. The RAPNO working group recommendations highlighted the lack of standard response criteria in clinical trials of pLGG as well as the biologic difference between pediatric and adult gliomasAlthough responses to tovorafenib generally occurred early, the kinetic analysis of tumor size over time per RAPNO and RANO-LGG criteria revealed that some patients who remained on treatment after an initial assessment of radiographic PD subsequently had marked tumor shrinkage, suggestive of a delayed response to treatment. This type of response pattern (that is, tumor flare or pseudoprogression) was previously observed in patients treated with immune checkpoint inhibitors, where some patients experience an initial increase in tumor size, followed later by an objective responseBy using both T1-weighted contrast-enhanced (RANO-HGG) and T2/FLAIR-based (RAPNO and RANO-LGG) approaches, the current trial assessed the impact of tovorafenib on different aspects of pLGG tumor biology and response. Despite the unique challenges of ascertaining an optimal, single set of response assessment criteria for this heterogeneous disease, confirmed responses to tovorafenib over time were observed across three different neuro-oncology response assessment criteria. To our knowledge, this is the first trial to report outcomes for these three criteria for a large, uniformly treated patient group.The main limitation of the current trial is that it is a single-arm clinical trial. However, this design was considered both sufficient and necessary due to the lack of a SOC for most patients with relapsed/refractory pLGG. In addition, there was a lack of diversity in relation to ethnicity/race of the patient population. The efficacy results of tovorafenib in FIREFLY-1 are similar to those in earlier non-registrational studies investigating MAPK inhibitors in this setting. The phase 2 trial of the MEKi selumetinibThe safety and tolerability profile of tovorafenib monotherapy in children and young adults with pLGG was encouraging, with TRAEs being predominantly grade 1 or 2 and only nine (7%) of 137 patients discontinuing due to a TRAE. The most common TRAEs of any grade, excluding laboratory abnormalities, were hair color changes, fatigue, maculopapular rash, dry skin, acneiform dermatitis, pruritus and paronychia. Although grade 1 and 2 laboratory abnormalities were commonly reported as AEs, most were not associated with any clinical symptoms or need for clinical intervention or change in therapy. The most common grade ≥3 TRAEs included elevated CPK, anemia and maculopapular rash. Other common grade ≥3 TEAEs (not assessed as related to tovorafenib), including seizures, were consistent with effects of the underlying disease.Overall, the AEs were consistent with the tovorafenib phase 1 trial in adults dosed once weekly and similar to other targeted agents used as pLGG therapy, including MAPK inhibitors, with some notable exceptionsThere were no on-trial treatment-related deaths, and TRAEs requiring discontinuation were infrequent. Intratumoral hemorrhage was reported in 15 patients and led to discontinuation of therapy in three patients. However, half (eight of 15) of the patients with intratumoral hemorrhage were asymptomatic, with areas of tumor hemorrhage identified on routine trial MRI only. Three of the seven patients with symptomatic tumor hemorrhage had tumor bleeds assessed by the investigator as consistent with the natural history of their underlying tumor and not related to tovorafenib. Of the four patients in which the symptomatic hemorrhage was considered by the investigator to be possibly related to tovorafenib, two patients had a history of tumor hemorrhage before starting the study; the third patient had a disseminated tumor with leptomeningeal disease; and the fourth patient had bone marrow failure secondary to prior treatment with multiple alkylating agents that was diagnosed before the onset of tumor hemorrhage. Although the incidence of intratumoral hemorrhage in this patient population is not well described, case reports suggest that the tumor hemorrhage risk across pLGG tumor types with heterogenous histology, morphology and prior interventions may be underappreciatedDecreases in growth velocity were observed in children treated with tovorafenib. Among patients with complete endocrinology assessments reported, radiographic studies of the wrist supported conservation of growth potential with no advancement of bone age or evidence of premature fusion of growth plates. Furthermore, patients with available data after discontinuation of tovorafenib in the setting of FIREFLY-1 and prior studies show various degrees of recovery of growth velocity, including achievement of catch-up growth. A more detailed analysis of growth during and after treatment with tovorafenib is planned. Notably, children with cancer, and with midline CNS tumors such as pLGG, commonly develop endocrine abnormalities that may impact growth trajectories and the likelihood of achieving genetic potential for height. In one report, nearly half of children with hypothalamic/chiasmatic gliomas developed at least one endocrine disorder, most commonly a growth hormone deficiencyCollectively, these results show that tovorafenib monotherapy was generally well tolerated and demonstrated encouraging evidence of clinically meaningful, rapid and durable clinical activity in children and young adults with 