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BGB-283 effective against tumors with BRAF, RAS mutations
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NEW ORLEANS — An investigational agent designed to target the RAF family of proteins demonstrated clinical activity in patients with cancer who harbored BRAF, KRAS or NRAS mutations, according to findings presented at the American Association for Cancer Research Annual Meeting.
Researchers reported a 62% disease control rate with BGB-283 (BeiGene). The agent also appeared well tolerated.
Jayesh Desai
BRAF mutations contribute to cancer cell proliferation in several cancer types, including thyroid cancer, colorectal cancer and melanoma.
BGB-283 has demonstrated activity against BRAF V600E mutations — the most common type of BRAF mutation observed in melanoma — as well as other RAF family proteins, according to study background.
Jayesh Desai, FRACP , medical oncologist at The Royal Melbourne Hospital in Australia, and colleagues hypothesized the agent may be an effective treatment for cancers with RAS mutations.
Their analysis included 31 patients. Of these, 18 had KRAS mutations, nine had BRAF mutations (BRAF V600E, n = 7; BRAF non-V600, n = 2) and three had NRAS mutations. One patient had NRAS and BRAF non-V600 mutations.
They received BGB-283 in once-daily doses that ranged from 5 mg to 60 mg. Researchers determined 40 mg daily was the maximum tolerated dose.
Desai presented data from 29 evaluable patients.
Researchers reported three (10.3%) confirmed partial responses. They included one person with BRAF V600E-positive melanoma, one person with KRAS–mutated endometrial cancer and one person with BRAF V600E-positive thyroid cancer. One patient (3.4%) with KRAS–positive non–small cell lung cancer achieved unconfirmed partial response.
The responder with KRAS–mutated endometrial cancer had a response duration of 411 days and a PFS duration of 455 days. All other partial responses exceeded 200 days and were ongoing at the time of data cutoff.
Fourteen patients (48.2%) demonstrated stable disease. Three of these patients had remained on treatment for more than 300 days at data cutoff.
The agent also appeared safe, researchers said.
The most common adverse events were fatigue (68%), anorexia (48%), constipation (42%), thrombocytopenia (39%), nausea (39%), vomiting (39%), dermatitis acneiform (39%), hand–foot syndrome (35%), hypertension (35%) and dysphonia (32%).
The most common grade 3 or grade 4 treatment-related adverse events were thrombocytopenia (13%), fatigue (10%) and increased alanine aminotransferase levels (10%).
More than 30% of malignancies in humans — including many colorectal, lung and pancreatic cancers — are driven by RAS gene mutations, according to NCI. Because RAS–mutant cancers are challenging to treat, the antitumor activity BGB-283 showed in this patient population is “very encouraging,” Desai said. However, the results must be confirmed in a larger cohort.
“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 RAS mutations and for different types of cancer,” Desai said in a press release. “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.” – by Mark Leiser
Reference:
Desai J, et al. Abstract CT007. Presented at: American Association for Cancer Research Annual Meeting; April 16-20, 2016; New Orleans.
Disclosure: BeiGene funded this study. Desai reports no relevant financial disclosures.