ROAR Study Update Solidifies Benefit of Dabrafenib/Trametinib in BRAF V600E+ ATC

The combination of dabrafenib (Tafinlar) and trametinib (Mekinist) has demonstrated promising antitumor activity in patients with BRAF V600E-mutated anaplastic thyroid cancer (ATC), according to findings from the phase 2 ROAR study (NCT02034110) of patients with various BRAF V600E-mutant rare cancers.¹

A human thyroid | Image Credit: © Rasi - www.stock.adobe.com

Initial results from the ROAR study led to the FDA’s accelerated approval of dabrafenib/trametinib in 2022 for the treatment of patients with unresectable or metastatic solid tumor harboring a BRAF V600E mutation. Results from 206 patients, including 36 patients with ATC were published in Nature Medicine. These were the final data on the primary end point of overall response rate (ORR), and the secondary end points of duration of response (DOR), progression-free survival (PFS), overall survival (OS), and the incidence of adverse events
(AEs).

Among the 36 patients in the ATC cohort who were treated with dabrafenib/trametinib, the ORR per investigator assessment was 56%. Among the responders, 8% of patients achieved a complete response (CR). Partial responses (PR) were seen in 47% of patients, and the remaining patients had either stable disease (SD; 31%), or progressive disease (PD; 11%), according to the investigators’ assessment. The median duration of response (DOR) by investigator assessment was 14.4 months (7.4 months to not reached [NR]).

The independent radiology assessment, however, showed an ORR of 53%. The CR rate observed was 6%, the PR rate was 47%, the SD rate was 22%, and the PD rate was 22%. The median DOR observed was 13.6 months (range, 3.8-39.4). The median DOR by independent radiology assessment was 13.6 months (range, 3.8-39.4).

Survival results showed a median PFS of 6.7 months (range, 4.7-13.8), as assessed by investigators. Per independent radiology assessment, the median PFS was 5.5 months (range, 3.7-12.9). The median OS was 14.5 months (95% CI, 6.8-23.2).

All 36 patients in the ATC cohort experienced any-grade AEs. The most frequent AEs, occurring in more than 20% of patients, included pyrexia (47.2%), anemia (36.1%), fatigue (36.1%), nausea (33.3%), and rash (27.8%).

AEs of special interest that occurred frequently among patients with ATC in the study included skin toxicity (50.0%), pyrexia (47.2%), and bleeding (33.3%). Commonly occurring serious AEs in the ATC cohort were pneumonia (22.2%) and pleural effusion (8.3%). Of all the serious AEs observed in the ATC group, pyrexia, decrease in neutrophil count, and leukopenia were considered to be treatment related.

Notably, 66.7% of patients with ATC died during the study. Primary causes of death were non-cardiovascular cause (58.3%) and ATC (55.6%). AEs leading to treatment discontinuation occurred in 16.7% of patients, and these AEs included dyspnea and pleural effusion in 5.6% of patient each, as well as nausea, decrease in ejection fraction, and pneumonia, each occurring in 2.8% of patients.

Overall, 50% of patients in the ATC cohort of the ROAR study were White and 47% were Asian; however, race/ethnicity information was missing for 6% of patients. Patients had a mean age of 69.6 years, with the majority of patients being between the ages of 65 and 74 years old. Males made up 44% of the ATC cohort, and females made up 56%.

At baseline, 83% of patient in the ATC cohort had an ECOG performance score of 1, while 11% had a score of 0, and the remaining 6% had a score of 2. The time since last diagnosis was 125.0 days. All patients in the ATC cohort had measurable disease at the time of screening, and 81% had non-target lesions at that time. Ninety-seven percent of the patients had stage stage IVC disease, and 3% had stage IV.

In terms of prior treatment, 50% of patients received 1 prior radiotherapy, 31% had 2, and 19% had 0. Prior anti-cancer therapy was a prior therapy for all patients in the ATC cohort, with a large percent of patients having received chemotherapy (98%), radiotherapy (83%), and surgery (83%).

Results from the ROAR study, compared with the historical control, showed an ORR of 15% in patients with ATC². The activity of dabrafenib/trametinib is clinically meaningful, according to the study authors.¹ The study also underscores the importance of biomarker-based treatment of rare cancers, they added.

_REFERENCES:

_{1. Subbiah V, Kreitman RJ, Wainberg ZA, et al. Dabrafenib plus trametinib in BRAFV600E-mutated rare cancers: the phase 2 ROAR trial. Nat Med. 2023;29(5):1103-1112. doi:10.1038/s41591-023-02321-8}

_{2. Subbiah V, Kreitman RJ, Wainberg ZA, et al. Dabrafenib and trametinib treatment in patients with locally advanced or metastatic braf v600–mutant anaplastic thyroid cancer. J Clin Oncol. 2018;36(1):7-13. doi:10.1200/JCO.2017.73.6785}