Tumor Agnostic Approval Targets BRAF V600E–Mutant Disease

The FDA has granted accelerated approval to the combination of dabrafenib (Tafinlar) and trametinib (Mekinist) for adult and pediatric patients 6 years or older with unresectable or metastatic BRAF V600E–mutant solid tumors. Patients must have been disease progression following prior treatment and have no satisfactory treatment options. The safety and efficacy of the combination were evaluated in 131 adult patients from open-label, multiple cohort trials ROAR (NCT02034110) and NCI-MATCH (NCT02465060) and 36 pediatric patients from the CTMT212X2101 trial (NCT02124772).

The studies included 24 tumor types. Individuals in ROAR had high-grade glioma (HGG), biliary tract cancer, low-grade glioma (LGG), adenocarcinoma of small intestine, gastrointestinal stromal tumor, and anaplastic thyroid cancer. NCI-MATCH Subprotocol H included patients with BRAF V600E–positive solid tumors (excluding melanoma, thyroid cancer, and colorectal cancer [CRC]), and the pediatric trial included patients with refractory or recurrent LGG or HGG.

The objective response rate (ORR) was 41% among the 131 adult patients (95% CI, 33%-50%). Among the highest representative tumor types, ORR was 46% (95% CI, 31%-61%) for biliary tract cancer, 33% (95% CI, 20%-48%) for HGG (combined adult and pediatric) and 50% (95% CI, 23%-77%) for LGG (combined adult and pediatric). Among all pediatric patients, the ORR was 25% (95% CI, 12%-42%) with 78% of patients have a response lasting at least 6 months and 44% of responders having a response lasting at least 24 months.

“This is a known [combination] that’s already been approved [by the FDA] for 3 different indications, the [adverse] effects are known and managed by oncologists, and we know that BRAF V600E are actionable across these 3 tumor types [melanoma, non–small cell lung cancer (NSCLC), anaplastic thyroid cancers],” Vivek Subbiah, MD, said. “This important tissue agnostic approval across solid tumors provides access to patients with rare malignancies.”

In an interview with OncologyLive^®, Subbiah, an associate professor and clinical medical director of the Clinical Center for Targeted Therapy in the Division of Cancer Medicine, at The University of Texas MD Anderson Cancer Center in Houston discussed the significance of the approval and future directions for tumor agnostic drug development.

What is the significance of the FDA approval of the combination in this population and how do you see it affecting current practice patterns?

The FDA granted accelerated approval to dabrafenib, which is a BRAF inhibitor, in combination with trametinib, which is a MEK inhibitor, for the treatment of adult and pediatric patients [age] 6 years [or older] with unresectable metastatic solid tumors that harbor the BRAF V600E mutation who have followed and progressed following prior treatment and have no satisfactory alternative treatment. The BRAF and MEK inhibitor combination is approved for melanoma, NSCLC, and anaplastic thyroid cancer. The lack of clinical benefit in BRAF inhibition and BRAF V600E-mutated CRC had prevented its tissue agnostic developing.

The MAP kinase pathway was first implicated in the pathogenesis of melanoma and since then, we have 3 different combinations that have shown activity and are FDA approved in melanoma specifically harboring BRAF V600E mutations. The main challenge is [targeted] BRAF V600E mutations [across] all malignancies. We reviewed case reports, outcomes of patients with BRAF-mutated nonmelanoma malignancies [and saw that] BRAF V600E mutations are prevalent across multiple nonmelanoma malignancies [with] more than 20 different tumor types harboring this mutation. They lead to oncogene addiction across all these tumor types and are clinically actionable in a broad variety and range of other and pediatric nonmelanoma malignancies. CRC remained an exception.

Please put the efficacy data in context, especially for some of the rare tumor types.

We put together 3 different clinical trials and the safety and efficacy were evaluated in 131 adult patients from open label, multi-cohort studies. The trials were the ROAR study, which is a rare oncology agnostic research study, the NCI-MATCH study, and a pediatric study. The pediatric study was supported by the COMBI-d and COMBI-v studies in melanoma and lung cancer which have been described extensively in literature and the product labeling.

The main study was a ROAR basket study which enrolled patients with BRAF V600E mutations across multiple tumor types such as LGG, HGG, biliary tract cancer, carcinoma of the small intestine, gastrointestinal stromal tumor, and anaplastic thyroid cancer. Part C and D of the pediatric study enrolled patients with BRAF V600E refractory or recurrent LGG and HGG. Based on the data of clinical benefit and the area of unmet need, the combination [of dabrafenib and trametinib] received additional agnostic approval across all solid tumors, with the exception of CRC, harboring BRAF V600E mutations.

What are the implications on routine diagnostics?

I think the combination of dabrafenib and trametinib demonstrates meaningful efficacy in multiple BRAF-mutant tumor types, including some patients with rare cancers who have no alternative treatment options. Physicians should consider a BRAF test as a routine diagnostic test step that could enable this new treatment option for patients with many solid tumors. Specifically, we need comprehensive next-generation sequencing in patients with solid tumors so that patients can benefit from BRAF targeted therapy.

Based on this approval, and others in the past, do you believe that the field of oncology is headed toward more tumor agnostic approvals? Or will it be used as a tool for rarer subsets?

I think it’s going to be a combination of both, think there will be more tissue agnostic approvals, especially for targets that share biomarkers across different tumor indications. We see these biomarkers in rare cancers more than common cancers. We are learning [about these] are new approvals, new targets, and new medications.

The first ever tissue agnostic agent that was approved was immunotherapy, pembrolizumab [Keytruda], for [patients with] mismatch repair deficient [dMMR] microsatellite instability-high tumors. The second drug was larotrectinib [Vitrakvi] for antifusion paths to solid tumors. The third drug was entrectinib [Rozlyrek], and subsequently pembrolizumab also received approval for [patients with high] tumor mutation burden. More recently, dostarlimab-gxly [Jemperli] was approved in a histology agnostic manner for patients with dMMR and there is a VHL-targeted agent also approved with a tissue agnostic indication.

The new kid on the block, BRAF V600E, has been a specific target for the past decade, but for patients beyond melanoma, lung cancer, or anaplastic thyroid cancer, those harboring BRAF mutations did not have any approved therapy, especially patients with CRC, HGGs, or LGGs. This approval will provide access for these patients.

Is there anything else that you would like to add?

My personal belief is universal genomic testing is needed to move our needle against cancer. I think the more comprehensive tests we do in patients the earlier in the disease course, more patients will benefit from these therapies.

Reference

FDA grants accelerated approval to dabrafenib in combination with trametinib for unresectable or metastatic solid tumors with BRAF V600E mutation. FDA. June 23, 2022. Accessed July 26, 2022. bit.ly/3cIz4E6