On April 2, 2017 BeiGene, Ltd. (NASDAQ:BGNE), a clinical-stage biopharmaceutical company developing innovative molecularly-targeted and immuno-oncology drugs for the treatment of cancer, reported data from the Phase IB dose expansion study of RAF dimer inhibitor BGB-283 in patients with B-RAF or K-RAS/N-RAS mutated solid tumors in an oral presentation during a Clinical Trials Plenary Session at the 2017 American Association for Cancer Research (AACR) (Free AACR Whitepaper) Annual Meeting in Washington, DC (Press release, BeiGene, APR 2, 2017, View Source [SID1234518415]). BGB-283 is a novel inhibitor of RAF, in both its monomeric and dimeric forms, and has demonstrated activity in both B-RAF and K-RAS-mutated tumors in preclinical studies and in the Phase IA dose escalation portion of this Phase I study. In the Phase IB portion, BGB-283 has generally been well-tolerated at a dose of 30 mg once a day (QD) and has continued to show antitumor activity not only in subjects with B-RAF V600-mutated solid tumors, but also in subjects with K-RAS-mutated solid tumors.

Schedule your 30 min Free 1stOncology Demo!
Discover why more than 1,500 members use 1stOncology™ to excel in:

Early/Late Stage Pipeline Development - Target Scouting - Clinical Biomarkers - Indication Selection & Expansion - BD&L Contacts - Conference Reports - Combinatorial Drug Settings - Companion Diagnostics - Drug Repositioning - First-in-class Analysis - Competitive Analysis - Deals & Licensing

                  Schedule Your 30 min Free Demo!

"BGB-283 appears to have a desirable risk-benefit profile in the combined efficacy and safety data from the Phase IA and IB parts of this study. Clinical activity has been observed for BGB-283 not only in B-RAF V600-mutated melanoma, thyroid cancer, and ovarian cancer, but also in K-RAS-mutated non-small cell lung cancer and endometrial carcinoma. These observations warrant further investigation of BGB-283 in the clinic," commented Jayesh Desai, MD, FRACP, a medical oncologist at The Royal Melbourne Hospital and Peter MacCallum Cancer Centre in Melbourne, Australia, and coordinating principal investigator of the study.

"Data from the Phase IB trial of BGB-283 further supported the anti-tumor activity in both RAF- and RAS-mutated tumors that we observed in the Phase IA study. We look forward to continuing clinical development of BGB-283 as either a single agent or in combination with other targeted or immuno-oncology agents," commented Amy Peterson, MD, Chief Medical Officer, Immuno-oncology at BeiGene.

Summary of Results

The multicenter, open-label Phase I trial of BGB-283 conducted in Australia and New Zealand is comprised of two parts – Phase IA (dose-escalation) and Phase IB (dose-expansion) in patients with B-RAF or K-RAS/N-RAS mutated solid tumors or patients with pancreatic cancer. The dose-expansion portion of the trial was designed to evaluate the safety and efficacy of BGB-283 at the recommended Phase II dose of 30 mg QD established in the Phase IA part of the trial. The expansion cohorts include patients with B-RAF V600-mutated cancers including melanoma, either naïve or having developed resistance to existing B-RAF or MEK inhibitors, colorectal cancer (CRC), non-small cell lung cancer (NSCLC), and papillary thyroid cancer (PTC), as well as patients with other B-RAF-mutated solid tumors. They also include patients with K-RAS/N-RAS-mutated endometrial cancer, NSCLC, and CRC, as well as patients with other K-RAS/N-RAS-mutated solid tumors and patients with pancreatic cancer.

The safety analysis, which included 96 patients as of the September 12, 2016 cut-off, suggested that BGB-283 was generally well-tolerated at 30 mg QD, with most drug-related adverse events (AEs) being grades 1 or 2 in severity. The most frequent drug-related AEs (≥10%) of any grade were fatigue (38.5%), dysphonia (26.0%), decreased appetite (21.9%), palmar-plantar erythrodysaesthesia syndrome (21.9%), thrombocytopenia (19.8%), dermatitis acneiform (17.7%), diarrhea (16.7%), rash (16.7%), nausea (15.6%), hypertension (11.5%), and glossodynia (10.4%). The most frequent drug-related grade 3-4 AEs (≥2%, 2 patients or more) included fatigue (7.3%), hypertension (6.3%), thrombocytopenia (6.3%), pyrexia (3.1%), hyponatremia (2.1%), anemia (2.1%), neutropenia (2.1%), febrile neutropenia (2.1%), decreased platelet count (2.1%), increased alanine aminotransferase (2.1%), increased gamma-glutamyltransferase (2.1%), and sepsis (2.1%).

The cut-off for the efficacy analysis was September 17, 2016. In seven patients with B-RAF V600-mutated melanoma (including one V600K and one V600R) who were naïve to B-RAF or MEK inhibitors, there were three partial responses (PRs) and three cases of stable disease (SD). In three patients with B-RAF V600-mutated PTC, there was one PR and two cases of SD. In six patients with K-RAS-mutated NSCLC, there was one PR and two cases of SD. In ten patients with solid tumors with B-RAF non-V600 mutations or solid tumors with B-RAF V600 mutations that are not included in other cohorts, there were two PRs, in one patient with BRAF V600E-mutated melanoma and one with BRAF V600E-mutated ovarian cancer, and three cases of SD. In two patients with B-RAF V600-mutated NSCLC, there was one unconfirmed PR and one case of SD.

Additional cases of SD were observed in four of six melanoma patients with B-RAF V600-mutated melanoma who had responses to but developed resistance against B-RAF or MEK inhibitors, nine of 13 patients with B-RAF V600-mutated CRC, five of five patients with K-RAS-mutated endometrial cancer, 12 of 20 patients with K-RAS/N-RAS-mutated CRC, and 10 of 21 patients with other K-RAS/N-RAS-mutated solid tumors or pancreatic cancer.

In the Phase IA portion of the study, confirmed objective responses included a complete response in a patient with B-RAF V600E-mutated melanoma, and two PRs, one in a patient with B-RAF V600E-mutated thyroid cancer and one in a patient with K-RAS-mutated endometrial cancer.

About BGB-283

Discovered by BeiGene scientists, BGB-283 is a novel RAF inhibitor with unique RAF dimer and EGFR inhibition activities. BGB-283 has shown antitumor activities in preclinical models and in cancer patients not only in tumors with BRAF V600E mutations but also those with non-V600E BRAF mutations and KRAS/NRAS mutations.