BRAFV600E alterations are found in multiple cancer types. Final efficacy and safety data from the Phase II Rare Oncology Agnostic Research (ROAR) basket trial demonstrated the tumor-agnostic activity of dabrafenib, a BRAF kinase inhibitor, in combination with the MEK inhibitor trametinib among patients with BRAFV600E-mutated advanced rare cancers (Nat Med 2023; https://doi.org/10.1038/s41591-023-02321-8).
The study was conducted at 27 community and academic cancer centers in 13 countries, including The University of Texas MD Anderson Cancer Center, led by Vivek Subbiah, MD, who is now Chief of Early-Phase Drug Development for Sarah Cannon Research Institute, and examined the efficacy and safety of this targeted therapy combination in patients with a variety of BRAFV600E-mutated cancers, including anaplastic thyroid, biliary tract, gastrointestinal stromal tumor, adenocarcinoma of the small intestine, high- and low-grade glioma, hairy cell leukemia, and multiple myeloma.
In June 2022, the FDA granted accelerated approval to dabrafenib plus trametinib for the treatment of adult and pediatric patients (6 years of age or older) with unresectable or metastatic BRAFV600E-mutated solid tumors who have progressed following prior treatment and have no other treatment options. This approval is based on a pooled analysis of the ROAR trial data, coupled with findings from the NCI MATCH trial and a pediatric trial.
Previously, the ROAR study resulted in the June 2018 FDA approval of this combination treatment for patients with locally advanced or metastatic anaplastic thyroid cancer with BRAFV600E mutation and no acceptable locoregional therapeutic options. Additionally, promising activity in biliary tract cancer, as well as low-grade and high-grade gliomas, led to inclusion in the NCCN guidelines.
Due to the known resistance to BRAF inhibition, the combination of dabrafenib and trametinib is not indicated for patients with colorectal cancer. Dabrafenib is also not indicated for individuals with wild-type BRAF solid tumors.
"Precision oncology has revolutionized the management of many tumors. And we are entering an era of tissue agnostic precision medicine-meaning tumors are being treated not based on the histology of origin, but rather by the biomarkers they harbor," noted Subbiah while discussing his research with Oncology Times.
"BRAF mutations are detected in about 7-15 percent of all cancers, and the most common locus of the mutation is at position V600," he explained. "The mutation is seen in diverse cancers, including hairy cell leukemia (79%-100%), melanomas (40%-70%), papillary thyroid cancers (45%), ovarian cancers (35%), cholangiocarcinomas (5% to 7%), multiple myeloma (4%), and non-small cell lung cancers (1%-3%)."
BRAFV600 mutations are also found in rare and difficult-to-treat cancers, according to Subbiah, such as anaplastic thyroid cancers, gliomas, and sarcomas, among others. "In the ROAR study, we sought to determine if the combination of dabrafenib and trametinib is actionable across multiple tumor types harboring BRAF V600 mutation."
Research Methods
In this multicenter, single-arm, open-label, Phase II basket study, Subbiah and colleagues evaluated the efficacy and safety of dabrafenib plus trametinib in patients with BRAFV600E-mutated rare cancers. The study included the following patient cohorts: anaplastic thyroid carcinoma (ATC), biliary tract cancer (BTC), gastrointestinal stromal tumor (GIST), adenocarcinoma of the small intestine (ASI), low-grade glioma (LGG), high-grade glioma (HGG), hairy cell leukemia (HCL), and multiple myeloma. The primary endpoint was investigator-assessed overall response rate (ORR). Secondary endpoints included median duration of response, progression-free survival, overall survival, and safety.
Eligible patients were adults with a confirmed BRAFV600E-mutated tumor who had no standard treatment options and an ECOG performance status score of two or more. Study participants were administered oral dabrafenib (150 mg twice daily) and oral trametinib (2 mg once daily) on a continuous dosing schedule. Treatment continued until unacceptable toxicity, disease progression, or death.
The study allowed for dose adjustments and interruptions for patients who were unable to tolerate the protocol-specified dose until tolerability improved. Among patients who discontinued or withdrew from the study treatment, the researchers conducted follow-up visits within 28 days of the last dose, as well as every month for the first 6 months for dermatologic assessments and every 3 months for survival data.
Study Findings
Subbiah and colleagues screened 251 patients between April 17, 2014, and July 25, 2018, and 206 were enrolled in the study (36 ATC, 43 BTC, 1 GIST, 13 LGG, 45 HGG, 3 ASI, 55 HCL, and 10 multiple myeloma). The primary analysis cohort included a total of 108 patients and the expansion cohort included 98 patients.
The study authors confirmed BRAFV600E mutation status via a central laboratory in 92 percent, 91 percent, 62 percent, 93 percent, and 91 percent of patients with ATC, BTC, LGG, HGG, and HCL, respectively. BRAFV600E mutation status was identified in all patients with GIST, ASI, and multiple myeloma.
Researchers reported a median age of 60.5 years among study participants. Forty-one percent were 65 years or older. The majority of patients were male (56%) and White (78%). Thirty-five percent, 57 percent, and 8 percent of enrolled patients had an ECOG performance status of 0, 1, and 2, respectively.
The median duration of exposure was 12.5 months for dabrafenib and 12 months for trametinib across all patient groups. Two-thirds of patients were given dabrafenib (66%) and trametinib (65%) for more than 6 months. The median daily dose of dabrafenib and trametinib was 282.1 mg and 1.9 mg, respectively, according to the study authors who noted that a daily dose of 450 mg dabrafenib was administered in eight patients.
Among the enrolled patients, 111 (54%) died. Thirty-one percent withdrew due to the sponsor's decision to terminate the study and 13 percent withdrew consent. Data showed that the most common reason for treatment discontinuation was progressive disease.
To corroborate the results for investigator-assessed ORR, the study authors also centrally assessed ORR by independent radiology review for the ATC, BTC, ASI, LGG, and HGG patient cohorts. Subbiah and colleagues reported an ORR of at least 50 percent across all patient groups except for the high-grade glioma cohort (ORR >30%).
"The GIST cohort enrolled only one patient. With exposure to dabrafenib plus trametinib for 30 months, the patient had stable disease as per the investigator assessment," the research team noted. "The concordance rates for best response by investigator and independent radiology assessment were 66.7 percent, 58.1 percent, 66.7 percent, 46.2 percent, and 66.7 percent for the ATC, BTC, ASI, LGG, and HGG cohorts, respectively."
Researchers defined duration of response as the time from complete or partial response. Among responders in the ATC, BTC, ASI, LGG, HGG, and multiple myeloma cohorts, the median duration of response was 14.4 months, 8.9 months, not reached; 7.7 months, not reached; 31.2 months, not reached; and 11.1 months, respectively. The median duration of response for patients with HCL was not reached. Additionally, according to the study authors, the GIST patient did not have a complete or partial response.
Median progression-free survival was 6.7 months for ATC, 9 months for BTC, 9.5 months for ASI, 5.5 months for HGG, and 6.3 months for multiple myeloma. Due to the small number of patients, progression-free survival was not evaluated in the LGG and HCL patient groups. Among patients with ATC, BTC, HGG, and multiple myeloma, the median overall survival was 14.5 months; 13.5 months, not reached; 21.8 months, not evaluable; 17.6 months, not evaluable; and 33.9 months, respectively.
"In the ASI cohort, the median OS was 21.8 months," according to the researchers. "All three patients in the ASI cohort died during the study. OS could not be estimated owing to the low numbers of deaths in the LGG (n=4) and HCL (n=8) cohorts."
Adverse events were observed in 201 (97.6%) of all patients, regardless of the relationship to study treatment. The most common were pyrexia (n=113, 54.9%), fatigue (n=87, 42.2%), and nausea (n=86, 41.7%), Subbiah and colleagues stated.
Across all cohorts, a total of 181 (87.9%) patients reported adverse events of any grade related to the study treatment-either dabrafenib or trametinib. The most frequent were pyrexia (n=84, 40.8%), fatigue (n=53, 25.7%), chills (n=52, 25.7%), nausea (n=49, 23.8%), and rash (n=42, 20.4%). In the entire study population, 111 (53.9%) patients died. Of these, 20 (9.7%) died within 30 days from the last dose of the study treatment, according to the researchers who noted that the most common primary cause of death was disease progression in 90 (43.7%) patients.
"One (0.5%) patient died due to other cancer, and the cause of death was missing in seven (3.4%) patients," they said. "None of the deaths was reported to be related to the study drug."
Takeaways & Next Steps
When sharing the significance of these findings, Subbiah noted, "the use and approval of this combination as a tissue agnostic treatment for solid tumors is the result of more than 20 years of extensive research into BRAF mutation and human cancer, the underlying biological mechanisms that drive BRAF-mediated growth, and clinical testing and refinement of selective BRAF and MEK kinase inhibitors.
"The ROAR study, and subsequent FDA approval, marks a significant achievement in the field of oncology and represents a major milestone and step forward in our ability to treat cancer," he emphasized. "The data demonstrated consistently good response rates in various tumors, including rare diseases, and we can now offer this additional line of therapy to these patient groups."
The next step, according to Subbiah, is to go beyond patients with heavily pretreated cancers who do not have standard therapy options and evaluate the combination of dabrafenib plus trametinib among individuals with treatment-naive BRAFV600E-mutation positive cancers.
"Moving forward, we should also explore potential resistance mechanisms and the future landscape of BRAF-targeted therapies," he noted. "It is important to identify the resistance mechanisms of this combination in different tumor types.
"We need to offer comprehensive genomic testing to our patients," Subbiah concluded. "My personal opinion and belief is that genomics is the diagnosis. If we are going to win the war against cancer, we need to have every ounce of intelligence available and genomics as a part of diagnosis is the first step towards that goal."
Catlin Nalley is a contributing writer.
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