The new investigational anticancer therapeutic BGB-283, which targets the RAF family of proteins, was safe, tolerable, and showed signs of clinical activity in patients who had a range of types of cancer with mutations in BRAF, KRAS, and NRAS, according to results from a phase I clinical trial presented by Desai et al at the AACR Annual Meeting 2016 (Abstract CT005).
“BRAF gene mutations fuel cancer cell proliferation and survival in a number of types of cancer, including melanoma, thyroid, and colorectal cancers,” said Jayesh Desai, FRACP, a medical oncologist at The Royal Melbourne Hospital in Melbourne, Australia. “In melanoma, the BRAF V600E mutation predominates, and specific inhibitors of the BRAF V600E mutant protein have been approved for treating patients with melanoma with BRAF V600E gene mutations.
“BGB-283 works differently than the currently approved BRAF V600E inhibitors, inhibiting the activity of all RAF family proteins and the BRAF V600E mutant protein,” continued Dr. Desai. “Because of the way it works, we hypothesized that BGB-283 might have antitumor activity against cancers with non–BRAF V600E mutations and, because the effects of RAS mutations are funneled through BRAF family proteins, we thought it might have antitumor activity against cancers with RAS mutations too.”
As of October 31, 2015, Dr. Desai and colleagues had enrolled 31 patients with a variety of types of cancer with BRAF, KRAS, or NRAS mutations in the dose escalation portion of the phase I clinical trial. The patients were assigned one of seven doses of BGB-283, ranging from 5 milligrams taken orally once a day to 60 milligrams orally once a day.
The maximum tolerated dose was determined to be 40 milligrams of BGB-283 taken orally once a day.
Among 29 patients treated with BGB-283 who were evaluable for response, three had confirmed partial responses, one had an unconfirmed partial response, and 14 had stable disease. The three patients who had confirmed partial responses were diagnosed with melanoma with a BRAF V600E mutation, endometrial cancer with a KRAS mutation, and thyroid cancer with a BRAF V600E mutation. The patient who had the unconfirmed partial response was diagnosed with non–small cell lung cancer with a KRAS mutation. All partial responses were ongoing with duration of response lasting over 200 days at the time of data cutoff, except for the response for the patient with endometrial cancer, who had a duration of response of 411 days and progression-free survival of 455 days.
The dose-limiting toxicity was thrombocytopenia. The most common reported adverse events have been grade 1 and 2 fatigue, anorexia, constipation, thrombocytopenia, nausea, vomiting, and dermatitis acneiform. Grade 3 and 4 adverse events included thrombocytopenia, fatigue, and liver dysfunction.
“These results are very encouraging, especially seeing antitumor activity against RAS-mutant cancers, which are challenging to treat,” said Dr. Desai. “However, we need to confirm our results in larger numbers of patients.”
According to the National Cancer Institute, more than 30% of all human cancers, including a large percentage of pancreatic, lung, and colorectal cancers, are driven by RAS gene mutations, but so far, researchers have been unable to develop effective therapeutics to block mutant RAS proteins.
“We need to develop a better understanding of the biology of RAS-mutant cancers, because emerging evidence suggests that they 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, because 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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