Dabrafenib Plus Trametinib Provides Benefit Across Glioma Subtypes

Dual inhibition of the MAPK pathway using the BRAF and MEK inhibitors dabrafenib (Tafinlar) and trametinib (Mekinist), respectively, resulted in durable clinical benefit for patients with BRAF V600E mutant low- and high-grade glioma. Results of the 2 cohorts from the phase 2 ROAR study (NCT02034110) were virtually presented by Vivek Subbiah, MD, at the AACR Annual Meeting 2021.

“BRAF V600E is an actionable driver mutation and should be considered for routine testing in glioma patients,” Subbiah said. “Dabrafenib and trametinib should be considered a meaningful therapeutic option for these patients.” Subbiah is an associate professor in the Investigational Cancer Therapeutics Department, and the center clinical medical director of the Clinical Center for Targeted Therapy, Cancer Medicine Division, at The University of Texas MD Anderson Cancer Center.

ROAR was a nonrandomized, open-label basket study of dabrafenib and trametinib in patients with BRAF V600E mutation–positive rare cancers. Thirty-seven patients with glioma were enrolled and included in the primary analysis. Those patients with World Health Organization (WHO) grade 1 or 2 glioma were classified as having low-grade glioma (LGG; n = 13) and those with WHO grade 3 or 4 grade glioma were classified as having high-grade glioma (HGG; n = 24). An expansion cohort of 21 patients with high-grade glioma was also included in the analysis (n = 21).

Patients received dabrafenib 150 mg twice daily and trametinib 2 mg once daily until unacceptable toxicity, disease progression, or death. As of September 14, 2020, the median follow-up for the HGG cohort was 12.7 months and 32.2 months for the LGG cohort. The primary end point was investigator-assessed objective response rate (ORR) and the secondary end points included progression-free survival (PFS), duration of response (DOR), and overall survival (OS).

HGG Cohort

The best overall response for each cohort was assessed by response assessment in neuro-oncology criteria. In the HGG cohort, the investigator-assessed ORR was 33% (95% CI, 20.0%-49.0%) with a complete response (CR) rate of 7% and a partial response (PR) rate of 27%. The median DOR was 36.9 months (95% CI, 7.4-44.2) with a 24-month DOR rate of 68.8% (95% CI, 36.4%-87.1%).

Data from the investigator-assessed survival analysis for the HGG cohort demonstrated a median PFS of 3.8 months (95% CI, 1.8-9.2) and a median OS of 17.6 months (95% CI, 9.5-45.2). The PFS 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. The 6-, 12-, and 24-month OS rates were 78.2% (95% CI, 62.3%-88.0%), 60.1% (95% CI, 43.3%-73.4%), and 41.8% (95% CI, 26.3%-56.5%).

LGG Cohort

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

The median PFS and OS were not reached according to data from the survival analysis of the LGG cohort. The PFS 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 6-, 12-, 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%).

Subbiah also presented post hoc efficacy analysis for the HGG cohort. “Interestingly, efficacy outcomes were favorable in adolescent and young adult patients compared with those in older adult patients,” Subbiah said. Specifically, 22 patients were included in the adolescent/young adult age group and the analysis showed an ORR of 50% (95% CI, 28.2%-71.8%) compared with 17% (95% CI, 5.0%-38.8%) for 23 patients aged 40 years or older. Further, median PFS was 18.5 months (95% CI, 5.5-41.4) for adolescent/young adult patients versus 1.7 months (95% CI, 0.9-2.5) for adult patients and overall survival was 45.2 months (95% CI, 17.9-not reached) and 8.7 months (95% CI, 3.7-11.7), respectively.

The median age for patients in the HGG cohort was 42 years (range, 18-72) and 69% of patients had glioblastoma histology (n = 31). Meaningful efficacy was also reported for patients with glioblastoma 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 for the HGG cohort was 6 months (range, 1-56).

Patients in the LGG had a median age of 33 years (range, 18-58) and a median duration of exposure of 26 months (range, 1-72). As of the data cutoff, 35 patients in the HGG cohort had discontinued therapy, 6 remained on treatment, and 4 were in follow-up. In the LGG cohort, 7 patients discontinued therapy, 5 remained on treatment, and 1 was in follow-up.

The most common grade 3/4 adverse effects (AEs) reported for all patients (N = 58) were fatigue (9%), neutrophil count decreased (9%), headache (5%), and neutropenia (5%). Further, the most common any-grade AEs included fatigue (50%), headache (43%), nausea (34%), and pyrexia (33%). Twenty-two patients (38%) had dose reductions, interruptions were reported for 24 patients (41%), and permanent discontinuation was reported for 5 patients (9%).

NGS Analysis Poses Unanswered Clinical Questions

Baseline tissue samples for 23 patients in the HGG (n = 19) and LGG (n = 4) cohorts were analyzed by next-generation sequencing (NGS) prior to therapy using a panel of 570 genes. For those in the HGG cohort, genetic alterations were found most frequently in PTEN, ATRX, and CREBBP, and copy number variations were observed in 10 patients, including MTAP or CDKN2A/B deletions in 5 patients. Subbiah noted that there were no IDH1/2 mutations in the analysis and that the tumor mutational burden was low (< 6 mutations/megabase) in all patient samples.

In the analysis of the LGG cohort, data showed copy number variations in 2 of 4 patients and no CDKN2A/B deletions were observed. Similar to the HGG cohort, no IDH1/2 mutations were detected, and the tumor mutational burden was low in all patient samples.

Subbiah noted in a discussion of the NGS data that identifying new targets for patients who have resistance to BRAF and MEK inhibition is an area that requires further explanation for this patient population. “For the patients who progressed [on dabrafenib and trametinib] it was challenging to acquire post-progression biopsies... I think we need to prospectively biopsy these patients pre- and post [therapy] to identify these mechanisms of resistance in the glioblastoma population,” Subbiah said.

Of the mutations and copy number variations observed in the baseline samples, Subbiah noted that none correlated with the response data to indicate those who would or would not have a response. “It would be good to analyze and access fresh tissue in the post-progression setting and analyze the mechanisms of resistance and if they are unique to a disease such as glioblastoma.”

Reference

1. Subbiah V, Stein A, van den Bent M, et al. ROR: dabrafenib plus trametinib in BRAF V600E–mutant high-grade and low-grade glioblastoma. Presented at: AACR Annual Meeting 2021; April 10-15, 2021; virtual. Abstract CT025.