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RAF Family Inhibitor Has Preliminary Activity in Multiple Types of Tumors

A multitargeted RAF inhibitor demonstrated activity in several types of advanced solid tumors associated with different mutations in the RAF family of genes, results of a preliminary clinical trial showed.

Of 29 evaluable patients, 3 had confirmed partial responses to treatment with BGB-283, 1 had an unconfirmed response, and 14 had stable disease. Responses have proved durable, and several patients have had prolonged periods of stable disease, according to a presentation at the American Association for Cancer Research Annual Meeting.

“These results are very encouraging, especially seeing antitumor activity against RAS-mutant cancers, which are challenging to treat,” said Jayesh Desai, MD, Medical Oncologist at the Royal Melbourne Hospital in Australia.

The RAF family of gene proteins—which includes BRAF, KRAS, and NRAS—are drivers of multiple types of cancer, including melanoma, thyroid, colorectal, and lung cancers. The BRAF V600E mutation predominates in melanoma, and several specific BRAF inhibitors have been developed to target the mutation.

In contrast to agents that target BRAF, BGB-283 inhibits the activity of all RAF family proteins, including the BRAF V600E mutant protein. Because the oncogenic effects of RAS mutations involve BRAF signaling, investigators hypothesized that BGB-283 would have activity against cancers driven by RAS mutations and signaling, said Dr Desai.

According to the National Cancer Institute, about one-third of all cancers are driven by RAS mutations. To date, however, no effective inhibitors of RAS have been developed.

Investigators enrolled 31 patients with previously treated advanced solid tumors and documented mutations in BRAF, NRAS, or KRAS. The primary objectives of the phase 1 trial were BGB-283 safety, tolerability, pharmacokinetics, recommended phase 2 dose, and preliminary clinical activity. Patients received 1 of 7 doses evaluated in the trial.

BGB-283 was well tolerated, said Dr Desai, and the maximum tolerated dose proved to be 40 mg once daily. Thrombocytopenia was the dose-limiting toxicity. The most frequent treatment-associated adverse events (all grades) were fatigue, anorexia, constipation, nausea, vomiting, dermatitis, hand-foot syndrome, hypertension, and dysphonia (all 30% or more of patients). The most common grade 3/4 treatment-emergent adverse events were thrombocytopenia (13%), fatigue (10%), and liver enzyme elevation (ALT, 10%).

Confirmed partial responses occurred in 1 patient with BRAF V600E–associated melanoma, 1 patient with KRAS-mutated endometrial cancer, and 1 patient with BRAF V600E–mutated thyroid cancer. The unconfirmed response occurred in a patient with KRAS-mutated non–small cell lung cancer. All the responses had a duration exceeding 200 days. The patient with endometrial cancer had an ongoing response at 411 days and a progression-free survival of 455 days. Additionally, several patients with stable disease had ongoing stability after more than 300 days.

In addition to assessing clinical activity, investigators evaluated the metabolic activity of BGB-283 by means of FDG-PET imaging performed prior to treatment and at the end of the first cycle of treatment. Results showed that 13 patients had partial metabolic responses.

Evaluation of BGB-283 is ongoing in an expansion study involving patients with several types of molecularly defined tumors.

“Emerging evidence suggests that RAS-mutant cancers are not all the same and that the signaling networks driving cancer cell proliferation and survival can be different for different RAS mutations and for different types of cancer,” said Dr Desai. “This has huge implications for using BGB-283 in the clinic, as we will likely need to understand the biology of each individual patient’s tumor to determine whether BGB-283 would be an appropriate treatment option.”

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