Discovery that more than 90% of papillary craniopharyngiomas carry BRAF V600E mutations led to a small, single-group phase II study in which of 16 evaluable patients, 15 (94%) had a response with a median tumour volume reduction of 91% at 4 months after the start of treatment.
At a median of 22 months after treatment, 12 of 16 patients (75%) had stable disease. Of the 12 with stable disease, 7 underwent radiotherapy immediately after receiving drug therapy and 5 received no additional intervention. The findings are published by Dr. Priscilla K. Brastianos of the Massachusetts General Hospital Cancer Center in Boston, MA, US, and colleagues on 13 July 2023 in The New England Journal of Medicine.
The authors wrote that although craniopharyngiomas are histologically benign tumours, they can cause profound clinical sequelae, both from mass effect at presentation and in terms of long-term complications associated with treatment. Two subtypes of craniopharyngioma, adamantinomatous and papillary, are managed identically with surgery followed by radiotherapy if gross total resection was not attained. Recurrences occur in 14-50% of cases. Even after multimodality treatment, many patients have lifelong sequelae and do not return to their pre-diagnosis functional status. There is no standard effective medical treatment for craniopharyngiomas.
Incomplete knowledge of the molecular drivers of craniopharyngiomas has historically delayed the development of effective treatments. Two histologic subtypes of craniopharyngiomas are recognised: adamantinomatous and papillary. In a genetic analysis of craniopharyngiomas, the same group previously found clonal BRAF V600E mutations in 94% of papillary craniopharyngiomas and activating CTNNB1 mutations in 96% of adamantinomatous craniopharyngiomas. Craniopharyngiomas are simple genetic tumours with a low mutation rate and no other known recurrent driver mutations.
In a patient who presented with multiply recurrent BRAF V600E–mutated craniopharyngiomas, treatment with BRAF and MEK inhibitor induced a rapid and dramatic reduction in tumour volume, and similar responses were described in other case reports.
In this small phase II, single-group study, the study investigators evaluated the combination of BRAF and MEK inhibition in patients with newly diagnosed BRAF-mutated papillary craniopharyngiomas. They report the results about papillary craniopharyngiomas not previously treated with radiotherapy. Combination of vemurafenib and cobimetinib was administered in 28-day cycles. The primary endpoint was objective response at 4 months as determined with the use of centrally determined volumetric data.
Of the 16 patients in the study, 15 (94%; 95% confidence interval [CI] 70 to 100) had a durable objective partial response or better. The median reduction in the volume of the tumour was 91% (range, 68 to 99). Responses were observed in both the enhancing and cystic components of the tumours and were durable.
The median follow-up was 22 months (95% CI 19 to 30) and the median number of treatment cycles was 8. Progression-free survival was 87% (95% CI 57 to 98) at 12 months and 58% (95% CI 10 to 89) at 24 months. Three patients had disease progression during follow-up after therapy had been discontinued; none have died.
The sole patient who did not have a response stopped treatment after 8 days due to side effects. Grade 3 side effects that were at least possibly related to treatment occurred in 12 patients, including rash in 6 patients. In 2 patients, grade 4 side effects (hyperglycaemia in 1 patient and increased creatine kinase levels in 1 patient) were reported; 3 patients discontinued treatment owing to side effects.
In an accompanied editorial article Prof. Jaishri O. Blakeley of the Johns Hopkins University School of Medicine in Baltimore, MD, US and Prof. Kevin Shannon of the University of California San Francisco in San Francisco, CA, US wrote that in contrast to many CNS tumours, papillary craniopharyngiomas are not within the blood-brain barrier. Because many histologically benign tumours respond poorly to conventional anticancer drugs, it was initially hypothesized that this would also be true for targeted agents. However, the results of this new study in BRAF V600E papillary craniopharyngiomas and other recent studies indicate that this is not the case. Genetically simple tumours are often dependent on single-driver mutations and are less prone than clonally complex cancers to rapidly develop resistance.
According to the editorialists, this study elegantly illustrates how repurposing drugs that were initially developed for common cancers benefits persons with rare tumours because of shared underlying molecular pathogenesis.
The study was funded by the US National Cancer Institute and others.
