达拉非尼联合曲美替尼对胶质瘤亚型有良好疗效

我们知道，达拉非尼联合曲美替尼可以联合治疗黑色素瘤。 But today the editor will introduce to you that dabrafenib combined with trametinib can treat glioma.神经胶质瘤神经胶质瘤简称胶质瘤，是发生于神经外胚层的肿瘤。胶质瘤大多缓慢发病，自出现症状至就诊时间一般为数周至数月，少数可达数年。肿瘤若有出血或囊变，症状会突然加重，甚至有类似脑血管病的发病过程。

Dual inhibition of the MAPK pathway using the BRAF and MEK inhibitors dabrafenib (Tafinlar) and trametinib (Mekinist) reduces BRAF Patients with V600E-mutated low-grade and high-grade gliomas experience durable clinical benefit. Vivek, MD Subbiah presented results from 2 cohorts of the Phase 2 ROAR trial (NCT02034110) at the 2021 American Association for Cancer Research (AACR) Annual Meeting.

The ROAR trial is a non-randomized, open-label basket trial. This trial investigated the effects of dabrafenib and trametinib on BRAF Outcomes in patients with V600E mutation-positive rare cancers. Thirty-seven patients with glioma were included in the preliminary analysis. Patients with World Health Organization (WHO) grade 1 or 2 glioma were classified as low-grade glioma (LGG; n=13), WHO 3级或4级胶质瘤患者分为高级别胶质瘤（HGG；n=24）。分析中还包括21例高级别胶质瘤患者的扩展队列（n=21）。

患者接受达拉非尼150 mg，每日两次，曲美替尼2 mg，每日一次，直到出现不可接受的毒性、疾病进展或死亡。 As of September 14, 2020, the median follow-up time was 12.7 months in the HGG group and 32.2 months in the LGG group. 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).

根据神经肿瘤学标准中的缓解评估来评估每个队列的最佳总体缓解。 In the HGG cohort, the investigators assessed the ORR to be 33% (95% CI, 20.0%-49.0%), the complete response rate (CR) to be 7%, and the partial response rate (PR) to be 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%).

The investigators evaluated data from the HGG cohort survival analysis and 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 PFS incidence rates at 6, 12, and 24 months were 42.2% (95% CI, 27.3%-56.3%), 34.7% (95% CI, 20.9%-49.0%), and 24.8% (95% CI, 13.0%-38.6%) respectively. 6、12、24个月的OS发生率分别为78.2%（95%CI、62.3%-88.0%）、60.1%（95%CI、43.3%-73.4%）和41.8%（95%CI，26.3%-56.5%）。

The researchers assessed that the ORR of the LGG cohort was 69.0% (95% CI, 38.6%-90.9%), the CR rate was 8%, and the PR rate was 46%. The median time to response was not reached, and the estimated 24-month DOR rate was 76.2% (95% CI, 33.2%-93.5%).

Based on data from the survival analysis of the LGG cohort, the median PFS and median OS were not reached. The PFS incidence rates at 6, 12, and 24 months were 84.6% (95% CI, 51.2%-95.9%), 69.2% (95% CI, 37.3%-87.2%), and 52.7% (95% CI, 23.4%-75.5%), respectively. The OS incidence rates at 6, 12, and 24 months 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.

The median age of patients in the HGG cohort was 42 years (range 18-72 years), and 69% of patients had glioblastoma histology (n=31). Patients with glioblastoma showed good response, 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). Median exposure in the HGG cohort was 6 months (range 1-56).

The median age of patients with LGG was 33 years (range, 18-58), and the median exposure time was 26 months (range, 1-72). At data cutoff, 35 patients in the HGG cohort had discontinued treatment, 6 patients were still on treatment, and 4 patients were on follow-up. In the LGG cohort, 7 patients discontinued treatment, 5 patients continued treatment, and 1 patient is on follow-up.

The most common grade 3/4 adverse reactions (AEs) in all patients were fatigue (9%), decreased neutrophil count (9%), headache (5%), and neutropenia (5%). Additionally, the most common adverse events of any grade included fatigue (50%), headache (43%), nausea (34%), and pyrexia (33%). The dosage of medication was reduced in 22 patients (38%), treatment was interrupted in 24 patients (41%), and medication was permanently discontinued in 5 patients (9%).

NGS analysis reflects unresolved clinical questions

Baseline tissue samples from 23 patients in the HGG (n=19) and LGG (n=4) cohorts were analyzed by next-generation sequencing (NGS) before treatment using 570 genes. In the HGG cohort, PTEN, ATRX, and CREBBP gene alterations were the most common, with 10 patients showing total sample variation, and 5 of them had MTAP or CDKN2A/B deletions. No IDH1/2 mutations emerged in the analysis, and tumor mutation burden was low (<6 mutations/megabase) in all patient samples. In the LGG cohort analysis, the data showed that 2 out of 4 patients had sample total variation, and no CDKN2A/B deletion was observed. Similar to the HGG cohort, no IDH1/2 mutations were detected and tumor mutation burden was low in all patient samples.

Summary

The editor believes that although there are still some unresolved problems with dabrafenib combined with trametinib in the treatment of glioma, this therapy is expected to become a treatment option for this type of patients in the near future.

References:

https://www.onclive.com/view/dabrafenib-plus-trametinib-provides-benefit-across-glioma-subtypes