RAF Family Inhibitor Has Preliminary Activity in Multiple Tumor Types

July 2016, Vol 7, No 6

The multitargeted RAF inhibitor BGB-283 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 the 29 evaluable patients who received BGB-283, 3 had confirmed partial responses, 1 had an unconfirmed response, and 14 had stable disease. The responses are durable, and several patients have had prolonged periods of stable disease, according to Jayesh Desai, MBBS, a medical oncologist at the Royal Melbourne Hospital in Australia, who presented the results at the 2016 American Association for Cancer Research annual meeting.

“These results are very encouraging, especially seeing antitumor activity against RAS-mutant cancers, which are challenging to treatment,” said Dr Desai.

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 this mutation.

In contrast to agents that target the BRAF protein, BGB-283 inhibits the activity of all RAF family proteins, including the BRAF V600E mutation. Because the oncogenic effects of RAS mutations involve BRAF signaling, the 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, approximately 33% of all cancers are driven by RAS mutations. To date, however, no effective inhibitors of RAS have been developed.

BGB-283 Demonstrates Safety and Efficacy

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

BGB-283 was well-tolerated, and the maximum tolerated dose was 40 mg once daily, said Dr Desai. 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 in ≥30% of patients). The most common grade 3 or 4 treatment-emergent adverse events were thrombocytopenia (13%), fatigue (10%), and elevation in liver enzyme levels (alanine transaminase, 10%).

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

In addition to assessing clinical activity, the researchers evaluated the metabolic activity of BGB-283 using 18F-fluorodeoxyglucose–positron emission tomography imaging performed before treatment and at the end of the first cycle of treatment. The 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. This has huge implications for using BGB-283 in the clinical, 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,” said Dr Desai.

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