达拉非尼联合曲美替尼治疗BRAF V600E突变型胶质瘤具有持久的临床受益

Results from the Phase 2 ROAR study (NCT02034110) presented at the 2021 American Association for Cancer Research (AACR) Virtual Meeting Show that dabrafenib (Tafinlar) combined with trametinib (Mekinist) treats BRAF In patients with V600E mutant low-grade and high-grade gliomas, dual inhibition of the MAPK pathway can have lasting clinical benefits.

The BRAF gene acts on the MAPK signaling pathway and affects cell division and differentiation. BRAF mutations often occur in many tumors, with the most common mutation being V600E. Dabrafenib is an inhibitor that targets BRAF mutations and can be used for BRAF Treatment of tumors with V600E gene mutations. MEK is a dual-specificity kinase that activates downstream ERK through phosphorylation, triggering a series of biological functions; trametinib is a MEK inhibitor that affects the MAPK pathway by acting on MEK protein, thereby inhibiting cancer cell proliferation.

"BRAF V600E is an actionable driver mutation and should be routinely tested in glioma patients, for whom dabrafenib and trametinib offer good treatment options," said Vivek, associate professor of research cancer therapeutics and medical director of the Targeted Therapeutics Clinical Center at The University of Texas MD Anderson Cancer Center. Dr. Subbiah said.

ROAR is a dabrafenib combination treatment for rare BRAF Nonrandomized, open-label basket study in patients with V600E mutation-positive cancer. The study included 37 glioma patients, of which 13 patients with grade 1 or 2 glioma were assigned to the low-grade glioma cohort (LGG cohort) according to World Health Organization (WHO) criteria, and 24 patients with grade 1 or 2 glioma were assigned to the low-grade glioma cohort (LGG cohort). Patients with grade 3 or 4 glioma were assigned to the high-grade glioma cohort (HGG cohort). In addition, the study also included 21 patients with high-grade glioma in the expansion cohort.

Patients received dabrafenib (dose 150 mg) twice daily and trametinib (dose 2 mg) until unacceptable toxicity, disease progression, or death. As of September 14, 2020, the median follow-up time for the HGG cohort was 12.7 months and the median follow-up time for the LGG cohort was 32.2 months. The primary endpoint is investigator-assessed objective response rate (ORR), and secondary endpoints include progression-free survival (PFS), duration of response (DOR), and overall survival (OS). The best overall response rate in each cohort was assessed according to Response Assessment in Neuro-Oncology (RANO) criteria.

For the HGG cohort, the investigator-assessed ORR was 33% (95% CI, 20.0%-49.0%), with a complete response rate of 7% and a partial response rate of 27%. The median DOR was 36.9 months (95% CI, 7.4-44.2), and the 24-month DOR rate was 68.8% (95% CI, 36.4%-87.1%). Survival analysis data evaluated by the investigators showed that the median PFS was 3.8 months (95% CI, 1.8-9.2) and the median OS was 17.6 months (95% CI, 9.5-45.2); the 6-month, 12-month and 24-month PFS rates were 42.2% (95% CI, 27.3%-56.3%) and 34.7% (95% CI, 20) respectively. .9%-49.0%) and 24.8% (95%CI, 13.0%-38.6%); the 6-month, 12-month and 24-month OS rates were 78.2% (95%C I, 62.3%-88.0%), 60.1% (95%CI, 43.3%-73.4%), and 41.8% (95%CI, 26.3%-56.5%).

For the LGG cohort, the ORR was 69.0% (95% CI, 38.6%-90.9%), with a complete response rate of 8% and an objective response rate of 46%; the median DOR was not reached, with an estimated 24-month DOR rate of 76.2% (95% CI, 33.2%-93.5%). Survival analysis data showed that the median PFS and median OS were not reached; the 6-month, 12-month and 24-month PFS rates were 84.6% (95%CI, 51.2%-95.9%), 69.2% (95%CI, 37.3%-87.2%) and 52.7% (95%CI, 2) respectively. 3.4%-75.5%); the 6-month, 12-month and 24-month OS rates were 92.3% (95%CI, 56.6%-98.9%), 83.9% (95%CI, 49.4%-95.7%) and 83.9% (95%CI, 49.4%-95.7%) respectively.

Dr. Subbiah also presented the results of the post hoc efficacy analysis of the HGG cohort, which showed that younger patients such as adolescents had better efficacy outcomes than older patients. Specifically, 22 patients were included in the young patient group and 23 patients aged ≥40 years were included in the older patient group. The ORRs were 50% (95% CI, 28.2%-71.8%) and 17% (95% CI, 5.0%-38.8%) respectively. In addition, the median progression-free survival and overall survival were 18.5 months (95% CI, 5.5-41.4) and 45.2 months (95% CI, 17.9-not reached), respectively, in the younger patient group and 1.7 months (95% CI, 0.9-2.5) and 8.7 months (95% CI, 3.7-11.7) in the older patient group.

The median age of patients in the HGG cohort was 42 years (range: 18-72 years), and 69% (31 patients) had glioblastoma. This type of patients also showed good efficacy, with an ORR of 32% (95% CI, 16.7%-51.4%), a median PFS of 2.8 months (95% CI, 1.8-13.7), and a median OS of 13.7 months (95% CI, 8.4-25.6). The median duration of exposure in the HGG cohort was 6 months (range: 1-56). The median age of patients in the LGG cohort was 33 years (range: 18-58 years), and the median duration of exposure was 26 months (range: 1-72 months). At the time of data cutoff, 35 patients in the HGG cohort stopped treatment, 6 patients were still receiving treatment, and 4 patients were in the follow-up period; in the LGG cohort, 7 patients stopped treatment, 5 patients were still receiving treatment, and 1 patient was in the follow-up period.

The most common grade 3/4 adverse reactions (AEs) reported in all patients (58 patients) were fatigue (9%), decreased neutrophil count (9%), headache (5%), and neutropenia (5%). In addition, the most common AEs of all grades were fatigue (50%), headache (43%), nausea (34%), and pyrexia (33%). The dose was reduced in 22 patients (38%), discontinued in 24 patients (41%), and discontinued in 5 patients (9%).

Prior to the trial, baseline tissue samples from a total of 23 patients in the HGG cohort (19 cases) and the LGG cohort (4 cases) were analyzed by next-generation sequencing (NGS) using a panel of 570 genes. For patients in the HGG cohort, the most common genetic alterations were in PTEN, ATRX, and CREBBP genes. Copy number variations were observed in 10 patients, of which 5 had MTAP or CDKN2A/B deletions. For the LGG cohort, copy number variations were observed in 2 patients, and no CDKN2A/B deletions were observed in 4 patients. In addition, no IDH1/2 mutations were found in either the HGG cohort or the LGG cohort, and the tumor mutation burden in all patient samples was low (<6 mutations/megabase in the HGG cohort).

Dr. Subbiah noted during the NGS data discussion that further research is needed to identify new targets for patients resistant to BRAF and MEK inhibitors. "For patients who progress on treatment with dabrafenib plus trametinib, obtaining post-progression biopsies is challenging. I think we need to prospectively biopsy these patients before and after treatment to identify mechanisms of resistance in these patients with glioblastoma."

Dr. Subbiah noted that none of the mutations and copy number variations observed in the baseline samples correlated with the response data, meaning that the occurrence of mutations and copy number variations may or may not lead to response. "It would be nice to be able to obtain and analyze fresh tissue in the post-progression setting, so that mechanisms of resistance could be analyzed and whether this resistance is unique to glioblastoma."

References:

https://www.cancernetwork.com/view/clinical-benefit-observed-with-dabrafenib-plus-trametinib-combo-for-glioma-subtypes