Background:
A craniopharyngioma is a primary brain tumor located on the pituitary-hypothalamic axis that can cause significant clinical sequelae. Surgery and/or radiation therapy often causes complications such as visual impairment, neuroendocrine dysfunction, and memory loss. Genotyping showed that more than 90% of papillary craniopharyngiomas carried the BRAF V600E mutation. This study evaluates the safety and efficacy of BRAF-MEK inhibitors in patients with papillary craniopharyngioma who have not received prior radiotherapy.
Research Methods:
1.Patient selection
Enrollment criteria included: papillary craniopharyngioma histologically confirmed to be BRAF V600E mutation;Has measurable lesions (two perpendicular diameters of 10mm);No prior radiotherapy or systemic**;Age 18 years;ecog≤2；Organs and bone marrow function normally;No evidence of intracranial hemorrhage within 4 weeks prior to enrollment;At least 21 days before the last surgery;No congestive heart failure, unstable angina, long QT syndrome, or uncontrolled cardiac arrhythmias.
2.Research**
28 days for a ** cycle. Patients received vemurafenib 960 mg orally twice daily for 28 days, combined with cobimetinib 60 mg orally once daily for 21 days. The study pre-stipulates that patients will receive final radiotherapy or surgery** after 4 cycles of vemurafenib in combination with cobimetinib**. The recommended radiotherapy regimen is 54 GY at a fraction dose of 18 gy。Patients may continue to receive vemurafenib plus cobimetinib** after 4 or 5 cycles if they benefit from vemurafenib plus cobimetinib** and if radiation therapy or surgery is not recommended due to severe adverse outcomes or patient refusal. If continuation of vemurafenib in combination with cobimetinib ** is approved, the regimen is continued as pre-specified until tumor progression, intolerable adverse events, or discontinuation for more than 28 days.
3.Endpoints and assessments
The primary endpoint was objective response rate (contrast-enhanced magnetic resonance imaging every 8 weeks, ** imaging assessment of tumor volume according to modified RANO criteria).
Secondary study endpoints included progression-free survival (PFS), overall survival (OS), response defined by enhanced tumor volume, response defined by no enhanced tumor volume, duration of response, and adverse events. In patients who respond to **, the duration of response is defined as the time interval from the first documented objective response to the occurrence of disease progression or death.
4.Statistical analysis
A two-stage design of Simon and an interim analysis of ineffectiveness were used. If a patient received at least one dose of the study**, their primary endpoint could be assessed. Of the 16 evaluable patients, if 3 patients achieved a complete response (CR) or partial response (PR) 4 months after the start of **, the study was considered to be ready to continue. After data were collected for 9 patients and followed for at least 4 months, an interim failure analysis was performed, and if no patient had an objective response, the regimen was considered ineffective in this population.
Findings:
1.Patients and**
Between February 20, 2018 and March 31, 2020, a total of 17 patients were included. One patient who was ineligible after enrollment due to concomitant use of a concomitant drug continued to receive vemurafenib in combination with cobimetinib** but was not included in the analysis of the primary endpoint. Thus, a total of 16 patients were eligible for the primary endpoint analysis.
The first nine patients were included in the interim analysis after seven months. The median age was 495 years old (range 33 to 83 years). ECOG 0 or 1 in 15 patients. The median tumor volume at baseline was 275 cm3。The median** number of cycles was 8 (range 0 to 19), all of which included at least one dose of one or two study drugs. The median number of cycles for both drugs** was 6 (range 1 to 12).
Patients who have ended the study protocol** continue to receive the following**: radiotherapy alone as per the protocol design (6 patients);Surgery after radiotherapy (1 person);After radiotherapy, dabrafenib (1);Out-of-protocol vemurafenib in combination with cobimetinib** (1 person). Seven patients did not receive any ** after discontinuing the protocol**.
2.Efficacy
*After 4 months, 15 out of 16 patients had CR or PR with an objective response rate of 94% (95% CI, 70%-100%), and one patient who did not respond stopped after **8 days due to toxic effects (grade 3 anaphylaxis and grade 2 acute kidney injury). Thus, all patients who completed at least one ** cycle responded to the BRAF-MEK inhibitor at 4 months after initiation of the combination regimen.
Median tumor volume decreased by 91% (range 68% to 99%) (Figure 1). Because craniopharyngiomas often have both enhancing and cystic non-enhancing components on imaging, the investigators also assessed the volume change for each component separately. Enhanced median tumor volume was reduced by 96% (range 80%-99%) and cystic non-enhancing tumor volume was reduced by 82% (range 41%-93%) compared to baseline.
Figure 1*Change in tumor volume after 4 months. The blue column represents 15 patients who had a partial response to vemurafenib plus cobimetinib**. The yellow column indicates that one patient withdrew after only 8 days** of toxic effects.
The 12-month progression-free survival rate was 87% (95% CI, 57%-98%) and the 24-month progression-free survival rate was 58% (95% CI, 10%-89%) (Figure 2A). Overall survival was 100% at both 12 and 24 months (Figure 2b).
Figure 2(a) Kaplan-Meier curves for progression-free survival, with 12- and 24-month progression-free survival rates of 87% and 58%, respectively;(b) Kaplan-Meier curve for overall survival, with 100% overall survival at 12 and 24 months.
At a median follow-up of 22 months (95% CI, 19-30), the estimated percentage of patients who continued to respond at 12 months was 93% (95% CI, 80% to 100%).
Three responding patients experienced disease progression during the follow-up period after discontinuation**. Of these, 2 patients developed disease progression after discontinuation of targeting** and before receiving surgery or radiotherapy. 1 patient continued to receive dabrafenib** followed by radiotherapy;The other patient received non-protocol vemurafenib in combination with cobimetinib**, followed by radiotherapy;The third patient did not receive any ** after disease progression.
Of the 7 patients who did not receive ** after discontinuation of vemurafenib in combination with cobimetinib, 6 had no tumor progression at a median follow-up of 23 months (95% CI, 19-not reached). No patients progressed during the study**.
3.Security
A total of 12 patients had grade 3 adverse events and 2 patients had grade 4 adverse events (determined by the ** physician to be very likely related to **). Three patients discontinued** due to adverse events, with a median time of 31 days. Grade 3 adverse events observed in 2 or more patients were rash, dehydration, elevated alkaline phosphatase levels, and QT interval prolongation. One patient had asymptomatic grade 4 elevated creatine kinase levels, and one patient had grade 4 hyperglycemia (likely related to **) (Table 3).
Table 3Grade 3 or 4 adverse events that may be associated with **.
4.Exploratory Analysis:
To assess whether the radiotherapy dose after vemurafenib in combination with cobimetinib ** would theoretically be smaller, the investigators measured the total volume of the target tumor on MRI images before and after **. Of the 14 patients evaluated, the median total volume before ** was 38 ml (range 0.)2-23.4), while the median total volume after ** is 03 ml (range 0-3.)2）。*The first 14 tumors were adjacent to the optic chiasm, and only 6 were adjacent to the optic chiasm.
Discuss
Although craniopharyngiomas are histologically benign tumors, they can cause serious clinical sequelae, either due to a mass effect at onset or due to long-term complications associated with **. To date, the method is the same for both subtypes of craniopharyngioma, and if it is not completely removed, surgery is followed by radiotherapy. **Rates can be as high as 14%-50%. Even after multimodality**, many patients have lifelong sequelae and do not return to their pre-diagnostic functional state. For craniopharyngioma, there is currently no standard effective drug** method.
In this study, vemurafenib was similar to that reported in patients with other tumors receiving these inhibitors. In addition, considering that radiotherapy in this patient population is associated with the risk of long-term toxic effects, the investigators found a significant reduction in the potential radiotherapy dose in patients receiving vemurafenib in combination with cobimetinib short-term**. Consistent with this observation, only 6 tumors were adjacent to the optic chiasm after **, while all tumors were adjacent to the optic chiasm at the front of **. The smaller amount of radiotherapy target remaining after a BRAF-MEK inhibitor** predicts less normal tissue being irradiated, so the risk of radiotherapy-related toxicity may be smaller.
Data from this study showed a significant response in all patients who received one or more cycles of BRAF-MEK inhibitors**, so a new approach to newly diagnosed papillary craniopharyngioma with BRAF-MEK inhibitors** is feasible. Physicians may consider a less invasive initial excision, or even a biopsy alone to diagnose tissues and confirm the BRAF V600E mutation, followed by a BRAF-MEK inhibitor**. Subsequently, definitive surgery or radiation**, or additional**or radiation** may be delayed to the tumor** or progression. Notably, 6 of the 7 patients who did not undergo local consolidation after receiving a BRAF-MEK inhibitor** did not experience tumor progression.
The investigator's trial had limitations. (1) This is a single-arm study excluding a control group. However, because craniopharyngioma is a rare tumor, researchers have tried to design studies with a small sample size considering feasibility. (2) The question of the ideal duration of targeting ** remains. As more data are collected at long-term follow-up, investigators may learn more about the durability of the response. (3) It is unclear whether the results of the study can be extended to ** craniopharyngioma. To address this issue, patients with craniopharyngioma after radiotherapy** will be enrolled in the second group of this study.
Conclusions of the study
Results from this small, single-arm study of patients with papillary craniopharyngioma showed that all patients who received at least one cycle of the BRAF-MEK inhibitor vemurafenib in combination with cobimetinib had durable partial or complete responses.
References: Brastianos PK, Twohy E, Geyer S, et al braf-mek inhibition in newly diagnosed papillary craniopharyngiomas. n engl j med. 2023;389(2):118-126
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Written by: Zhao Chuan, Gai Jingjing.
Reviewer: Zhang Junping.
Typesetting: Zhang Jingjing.