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Tovorafenib (DAY101)

RAF-altered pediatric low-grade glioma requiring first-line systemic therapy

Also known as TAK-580
Regulatory submission
Not announced
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Last updated
155 sources

Product information and disease descriptionPlace of product in therapyApproaches to treatmentCurrent treatment options and standard of care

Limitations of current therapies

21 evidence topics · 21 sources

Summary: limitations of chemotherapy, radiotherapy, and approved targeted therapy

First-line chemotherapy controls disease in fewer than half of treated participants over 5 years. In COG A9952 (274 participants), 5-year event-free survival (EFS) was 39% with carboplatin plus vincristine, and in SIOP-LGG 2004 (497 participants) 5-year PFS was 46% with vincristine plus carboplatin; in a Canadian cohort of 54 participants, 5-year PFS with weekly vinblastine was 53.2%. Carboplatin hypersensitivity occurred in 44 of 105 participants (41.9%) in a Canadian retrospective series and in 47% of 34 participants in a single-institution series, and 24 of 34 rechallenged participants (70.5%) had recurrent reactions. Chemotherapy requires weekly intravenous administration over 60 to 81 weeks, with central venous catheters recommended for infants and toddlers. Visual acuity worsened in 41% of participants with NF1-associated optic pathway glioma and 39% with sporadic optic pathway glioma after chemotherapy in the SIOP-LGG 2004 UK cohort. BRAF V600E tumors have a 10-year PFS of 27% after chemotherapy or radiation therapy.

Radiotherapy is associated with cognitive decline in children younger than 5 years, a 10-year cumulative incidence of growth hormone replacement of 48.9%, vasculopathy, and second neoplasms. Dabrafenib plus trametinib is approved for first-line use only in BRAF V600E tumors, and type I BRAF inhibitors are not indicated in BRAF fusion tumors, which comprise approximately 35% of pLGG. No targeted therapy is approved for first-line treatment of BRAF fusion-driven pLGG. After discontinuation of BRAF inhibition, 13 of 17 participants (76.5%) with BRAF V600E pLGG progressed at a median of 2.3 months, and the optimal duration of targeted therapy is not established.

Carboplatin hypersensitivity reactions

“Forty-four patients (41.9%) developed Cb HSR after a median of 10.5 infusions (range, 3-39 infusions).” (opens the source at this quote in a new tab)

“Thirty-four of 44 patients with Cb HSR were re-exposed to carboplatin, and 24 of 34 patients (70.5%) had recurrent Cb HSR.” (opens the source at this quote in a new tab)

“Those patients treated with 4-weekly single agent carboplatin had carboplatin allergy in 8% of cases whereas 68% of those treated with combined carboplatin and vincristine (every three weeks, according to the SIOP 2004 low grade glioma protocol) had carboplatin reactions (OR 23.6, P < 0.01). Desensitization was only successful in two out of 10 patients in whom it was attempted.” (opens the source at this quote in a new tab)

Treatment burden: intravenous administration, visits, and central venous access

“Treatment with V/C or VBL may be accompanied by significant adverse effects, including bone marrow toxicity, neurotoxicity, hearing loss, renal dysfunction, and allergic reactions [3]. The burden of toxicity, frequent hospital visits as well as a significant number of patients progressing after first-line treatment, motivated the search for alternative strategies. In addition, these chemotherapy regimens appear even less effective in infants with pLGG [11]” (opens the source at this quote in a new tab)

“Insertion of central venous catheter is recommended especially for infants and toddlers.” (opens the source at this quote in a new tab)

“Selumetinib requires monthly, shorter clinic visits and is taken orally with no requirement for central line placement as compared to weekly CV, bi-monthly bevacizumab/irinotecan and weekly vinblastine visits which often require a central line.” (opens the source at this quote in a new tab)

Visual outcomes after chemotherapy for optic pathway glioma

“Per subject, VA improved in 24%, remained stable in 35% and worsened in 41% of children with NF1-OPG and improved in 18%, remained stable in 43% and worsened in 39% of children with sporadic OPG.” (opens the source at this quote in a new tab)

“After a median 11-year follow-up, 81.5% showed abnormal vision, 45.7% were visually impaired, and 26% were bilaterally blind. Only 36% showed BCVA improvement, while 32% worsened.” (opens the source at this quote in a new tab)

Poor chemotherapy outcomes in BRAF V600E pLGG

“Patients with BRAF V600E PLGG exhibited poor outcomes after chemotherapy and radiation therapies that resulted in a 10-year progression-free survival of 27% (95% CI, 12.1% to 41.9%) and 60.2% (95% CI, 53.3% to 67.1%) for BRAF V600E and wild-type PLGG, respectively (P < .001).” (opens the source at this quote in a new tab)

Limitations of approved targeted therapy: fusion tumors, rebound, and unknown duration

“The use of type I BRAF inhibitors is limited to patients with tumors harboring a BRAF V600E mutation due to the risk of paradoxical activation of the MAPK pathway and accelerated tumor growth if used in patients with tumors harboring a RAF fusion, such as those involving BRAF or CRAF/RAF1 [23].” (opens the source at this quote in a new tab)

“However, data generated from ongoing studies of various MAPK pathway inhibitors have shown that responses in pLGGs driven by either BRAF V600E mutations (treated with type I RAF inhibitors and/or MEK inhibitors) or KIAA1549::BRAF fusions (treated with MEK inhibitors) are often only durable for as long as the drug can be administered [27, 28].” (opens the source at this quote in a new tab)

“After discontinuation of BRAF inhibition, 76.5% (13 of 17) of patients with PLGG experienced rapid progression (median, 2.3 months). However, upon rechallenge with BRAF inhibition, 90% achieved an objective response.” (opens the source at this quote in a new tab)

“While these treatments have heralded tremendous promise, challenges remain about how to best optimize their use, and the long-term toxicities associated with these inhibitors remain unknown.” (opens the source at this quote in a new tab)

“In the context of clinical paradigms favoring indefinite treatment, Dab-Tram is unlikely to prove cost-effective at the present price and would require a price reduction to facilitate sustained access.” (opens the source at this quote in a new tab)

Late effects of radiotherapy

“Cranial irradiation is also very effective against pLGG and has demonstrated improved PFS compared to conventional chemotherapy (62% versus 42% 10-year PFS compared to carboplatin/vincristine on HIT-LGG-1996) (13); however, radiation therapy is largely avoided in most sporadic pLGG and almost all NF1-associated pLGG due to the risk of significant late effects, including secondary malignancy, neurocognitive impairment, hormonal dysfunction, growth delay, vasculopathy and cerebrovascular injury (14–17).” (opens the source at this quote in a new tab)

Toxicity burden of first-line carboplatin and vincristine in the randomized comparison

“Carboplatin allergy was reported in 7 patients (21%) in the chemotherapy group.” (opens the source at this quote in a new tab)

“Permanent discontinuation because of adverse events was less common with dabrafenib plus trametinib than with chemotherapy (4% vs. 18%)” (opens the source at this quote in a new tab)

“The frequency of adverse events leading to a dose adjustment or interruption was similar in the two groups: 79% with dabrafenib plus trametinib and 79% with chemotherapy.” (opens the source at this quote in a new tab)

Grade 3 and 4 toxicity and carboplatin allergy rates with carboplatin and vincristine

“Allergic reaction to carboplatin was observed in 26 patients, and those with grade 3 or 4 discontinued carboplatin therapy. Peripheral neuropathy grade 3 and 4 occurred in 19% of patients. Hematological toxicity accounted for most of the grade 3 and 4 adverse events, in particular decrease absolute neutrophil count (94%), decreased platelets (21%), and anemia (35%)” (opens the source at this quote in a new tab)

“Toxicity profile was similar to the previous studies, most marked was carboplatin allergy affecting 53% of patients.” (opens the source at this quote in a new tab)

“Carboplatin hypersensitivity reaction occurred in up to 68% of treated patients and posed significant challenge to CV regimen application. Patients experiencing grade 3 and 4 reaction were required to discontinue the therapy.” (opens the source at this quote in a new tab)

“Desensitization might provide some benefit to 20–73% of patients” (opens the source at this quote in a new tab)

Progression-free survival falls with each subsequent line of chemotherapy

“However, Kandels et al. studied 96 patients who required second line chemotherapy. In this study, 3-year PFS for second line chemotherapy (28.1 ± 4.8%) was significantly lower when compared to first line chemotherapy (65.7 ± 2.7%). Progression-free survival rates declined with subsequent treatment-lines yet remaining higher for patients with NF1.” (opens the source at this quote in a new tab)

“In non-NF1-associated tumors, vinblastine monotherapy vs platinum-based chemotherapy was noticeably less effective when used as second-line treatment” (opens the source at this quote in a new tab)

Duration of carboplatin-based treatment and the proportion needing further therapy

“Carboplatin was administrated monthly in 46 patients (43.8%) patients for a median total duration of 11 months (range, 1–20 months) and weekly in 59 patients (56.2%) for a total duration of 12 months (range, 0.7–20.9 months)” (opens the source at this quote in a new tab)

“With a median follow-up of 5.1 years (range, 0.3–16.7 years) after diagnosis, 57 patients (54.3%) required further treatment for disease progression or relapse at a median of 21.3 months (range, 0.6–95.9 months).” (opens the source at this quote in a new tab)

Outcomes of carboplatin rechallenge with premedication or desensitization

“By using premedication alone, 10 patients (55.5%) were able to complete their carboplatin treatment, including 7 patients who had no further allergic manifestations (38.8%).” (opens the source at this quote in a new tab)

“The median number of additional carboplatin infusions delivered with altering Cb HSR therapies was 4 (range, 0.5–34 additional infusions).” (opens the source at this quote in a new tab)

“Because of recurrent hypersensitivity symptoms despite altering Cb HSR therapies, carboplatin was discontinued in 20 patients.” (opens the source at this quote in a new tab)

“Such strategies are time consuming, costly, and add a significant burden and anxiety to the patient, family, and caregivers.” (opens the source at this quote in a new tab)

Severity of carboplatin reactions and failure of a standard desensitization protocol

“Sixteen carboplatin hypersensitivity reactions were noted in the 34 children with low grade glioma. They occurred after a median of seven doses of carboplatin (range 3–14 doses). Three reactions were grade I allergic reaction, 10 were grade II allergic reaction, and three were grade III anaphylaxis according to CTCAE 4.0 criteria.” (opens the source at this quote in a new tab)

“Only two of 10 patients had no reaction to this rechallenge and one has since experienced a reaction, four doses after the successful rechallenge.” (opens the source at this quote in a new tab)

“Of the eight patients with further reactions, two were grade III anaphylaxis requiring adrenaline, and the remainder were grade II requiring symptomatic management only.” (opens the source at this quote in a new tab)

Unknown long-term effects of targeted agents

“The late effects of these systemic target agents are largely unknown due to its recent application and need further awareness.” (opens the source at this quote in a new tab)

“MAPK inhibition and PAN RAF inhibition lead to side effects mainly concerning the skin, nails, hair, gastrointestinal tract, blood counts, risen CPK increased weight, while for PAN-RAF inhibition, temporary decreased growth velocity has been described” (opens the source at this quote in a new tab)

“Until now, these side effects seem to be transient, but should be followed further.” (opens the source at this quote in a new tab)

Dose interruptions with each drug in the first-line randomized comparison

“Dose interruptions occurred in 56 of 73 patients (77%) receiving dabrafenib, 53 of 73 patients (73%) receiving trametinib, 23 of 33 patients (70%) receiving carboplatin, and 22 of 33 patients (67%) receiving vincristine” (opens the source at this quote in a new tab)

Severity of the first carboplatin reaction and worsening on re-exposure

“Of the 44 children who developed Cb HSR, the severity of the first reaction was grade I or II in 36 patients (82%), grade III in 6 patients (13.6%), and grade IV in 2 patients (4.6%)” (opens the source at this quote in a new tab)

“Upon re-exposure, 4 of 18 patients (22.2%) who received premedication alone and 7 of 12 patients (58.3%) who received both desensitization and premedication had worsening of their hypersensitivity symptoms” (opens the source at this quote in a new tab)

“It is even more noteworthy that 32% of patients presented with a more severe reaction upon re-exposure.” (opens the source at this quote in a new tab)

Limits of chemotherapy for preserving vision

“These findings raise the question as to whether chemotherapy is effective in preserving vision; it may well be that treatment after a certain point of visual deterioration cannot prevent further decline.” (opens the source at this quote in a new tab)

“A systematic review found that chemotherapy did not improve visual outcomes in 86% of children.” (opens the source at this quote in a new tab)

Timing of carboplatin hypersensitivity by schedule and its relation to cumulative exposure

“Cb HSR occurred significantly earlier during the weekly schedule, at median of 4.4 months (range, 0.4–15.4 months), compared with a median of 9.1 months (range, 3.1–14.6 months) on the monthly schedule (P = .02).” (opens the source at this quote in a new tab)

“The occurrence of hypersensitivity reaction was not related to a specific cumulative dose of carboplatin. The cumulative incidence of Cb HSR increased with the number of infusions without any plateau effect (Fig. 1).” (opens the source at this quote in a new tab)

“Age, NF1 status, and tumor location were not associated with Cb HSR. The schedule of carboplatin administration (weekly or monthly) did not significantly influence the incidence of Cb HSR.” (opens the source at this quote in a new tab)

Severity of the first hypersensitivity reaction and the failure of prophylactic premedication

“Of the 44 children who developed Cb HSR, the severity of the first reaction was grade I or II in 36 patients (82%), grade III in 6 patients (13.6%), and grade IV in 2 patients (4.6%) (Table 4).” (opens the source at this quote in a new tab)

“Prophylactic premedication did not prevent Cb HSR significantly and did not influence the severity of the reaction (grade III and IV toxicity; 40% vs 15.3%; P = .22).” (opens the source at this quote in a new tab)

Desensitization outcomes and the regimens used after carboplatin was stopped

“Among the 12 patients who underwent desensitization and premedication, only 1 patient (8.3%) was able to complete his carboplatin therapy (P = .018).” (opens the source at this quote in a new tab)

“Upon re-exposure, 4 of 18 patients (22.2%) who received premedication alone and 7 of 12 patients (58.3%) who received both desensitization and premedication had worsening of their hypersensitivity symptoms (P = .05).” (opens the source at this quote in a new tab)

“Four patients were observed without further chemotherapy, 2 patients underwent surgical resection, and 14 received another noncarboplatin-containing chemotherapy regimen, including 7 patients who received weekly vinblastine; 4 patients who received either combined thioguanine, procarbazine, and CCNU or combined thioguanine and PCV; and 3 patients who received another line of chemotherapy. The median duration of second-line chemotherapy was 7 months (range, 2–14 months). None of the patients received radiotherapy.” (opens the source at this quote in a new tab)

Progression during carboplatin treatment and total time on chemotherapy

“Fourteen (24.5%) progressions occured during administration of the carboplatin-based regimen.” (opens the source at this quote in a new tab)

“The median total duration of chemotherapy did not significantly differ for patients who did and did not experience Cb HSR (13.2 months and 11.3 months, respectively).” (opens the source at this quote in a new tab)