Abstract
The BRAF/MEK inhibitor combination dabrafenib/trametinib is effective in a wide array of rare BRAF-mutant cancers, according to findings from the NCI-MATCH trial presented at the 2019 American Society of Clinical Oncology Annual Meeting in Chicago, IL. In the trial, the combination elicited partial responses in 33% of patients and led to stable disease in another 39% of patients with rare BRAF V600E-mutant malignancies.
Novartis's BRAF/MEK inhibitor combination dabrafenib (Tafinlar)/trametinib (Mekinist) effectively treats a wide array of rare BRAF-mutant cancers, according to findings from the NCI-MATCH trial presented at the 2019 American Society of Clinical Oncology Annual Meeting in Chicago, IL, on June 3. In the trial, the combination elicited partial responses (PR) in 33% of patients and led to stable disease in another 39% with rare BRAF V600E–mutant malignancies, including gynecologic, gastrointestinal, central nervous system, and lung.
Since 2017, dabrafenib/trametinib has been approved to treat BRAF-mutant non–small cell lung cancer (NSCLC), melanoma, and anaplastic thyroid cancer based on high response rates and durable responses. Although not approved for other indications, the drugs have demonstrated clinical benefit in a few other cancers, such as glioma and cholangiocarcinoma. Despite having BRAF mutations, however, some cancers, such as colorectal cancer, do not respond well to the combination.
“Given [that] this potential heterogeneity and the specific sensitivity may depend on the specific disease setting, we feel it's critical to investigate this strategy of BRAF/MEK inhibition across a wide variety of tumor types,” said April Salama, MD, of Duke University School of Medicine in Durham, NC, who presented the results. Salama and her colleagues tested dabrafenib/trametinib in the NCI-MATCH study, a phase II basket trial in which patients are screened and assigned to receive targeted therapy based on tumor mutations.
The dabrafenib/trametinib arm of NCI-MATCH enrolled 33 previously treated patients with BRAF V600E mutations, 48% of whom had received at least three prior therapies; those who had received previous BRAF or MEK inhibitors were excluded. Patients had 17 different cancers; the trial excluded patients with colorectal cancer due to data suggesting resistance, as well as melanoma, thyroid cancer, and NSCLC (after the combination was approved for this indication).
Overall, the combination elicited PRs in 11 patients (33%) and stable disease in 13 more (39%). PRs were seen in five of six patients with gynecologic cancers, three of four with intrahepatic cholangiocarcinoma, two of three with central nervous system malignancies, and one with lung adenocarcinoma. Across cancers, patients had a median progression-free survival of 11.4 months and a median overall survival of 28.8 months. Side effects—most commonly fatigue, fever, chills, and nausea—were generally mild.
“This really showed the potential for these targeted combinations to be useful across a number of different tumor types,” said Scott Kopetz, MD, PhD, of The University of Texas MD Anderson Cancer Center in Houston, who was not involved in the trial. He added that these are the first findings on dabrafenib/trametinib in many of the cancers tested, where BRAF mutations are rare, as are the diseases themselves.
Michael Davies, MD, PhD, also of MD Anderson, noted that although the small number of patients makes drawing conclusions about efficacy in each cancer difficult, the findings “suggest that there is a broad clinical benefit that can be achieved even in highly refractory patients.” Davies was not involved in the trial, but he has advised companies developing BRAF and MEK inhibitors, including Novartis.
Kopetz and Davies wonder whether these findings and other data will prompt the FDA to consider a tissue-agnostic approval for patients with BRAF-mutant cancers, similar to that of pembrolizumab (Keytruda; Merck), which has been approved to treat microsatellite instability–high or mismatch repair–deficient solid tumors, regardless of their location.
“In my mind, this says that the default is that BRAF V600E–mutant tumors, regardless of histology, are going to respond, unless there are clinical data otherwise, such as in colorectal cancer,” Kopetz said. “There's clear and compelling activity in a molecularly selected subgroup that has impressive durability, and I think this challenges the assumption that we need to develop targeted BRAF therapies on an indication-by-indication basis.” –Catherine Caruso