AACR 2016: New RAF-targeted therapeutic shows early promise against tumours with BRAF and RAS mutations

17 Apr 2016

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 here at the AACR Annual Meeting 2016.

“BRAF gene mutations fuel cancer cell proliferation and survival in a number of types of cancer, including melanoma, and 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.

An interview with Dr Desai about this research can be viewed here.

“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 Desai. “Because of the way it works, we hypothesised that BGB-283 might have antitumour activity against cancers with non–BRAF V600E mutations and, because the effects of RAS mutations are funnelled through BRAF family proteins, we thought it might have antitumour activity against cancers with RAS mutations too.”

As of Oct. 31, 2015, 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.

“These results are very encouraging, especially seeing antitumour activity against RAS-mutant cancers, which are challenging to treat,” said Desai. “However, we need to confirm our results in larger numbers of patients.”

According to the National Cancer Institute, more than 30 percent 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 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.”

Source: AACR