Alexander M. Castellino, PhD

April 18, 2016

NEW ORLEANS — A new drug that targets the BRAF family of proteins is also active against some cancers with RAS mutations, according to results from a phase 1 study presented here at the American Association for Cancer Research 2016 Annual Meeting.

"BGB-283 is an inhibitor of BRAF and BRAF dimers, inhibits other RAF kinases beyond the V600E mutation, as well as EGFR," presenter Jayesh Desai, MD, a medical oncologist at The Royal Melbourne Hospital in Melbourne, Australia, told Medscape Medical News.

"Ultimately, it is an agent that targets other isoforms of RAF and is potentially a downstream inhibitor of RAS," he added.

Dr Desai explained that most kinases have inhibitors targeted to their ATP-binding pocket. The inhibition of RAS cancers has been problematic because they function differently — not through an ATP-binding pocket on the protein, but through a GTP-binding protein molecule.

"BGB-283 is promising, as it shows activity against RAF- as well as some RAS-mutant tumors," he said.

Details of the Study

Patients with advanced tumors with mutations in BRAF, KRAS, or NRAS that were refractory to treatment were enrolled in the study. Patients had melanoma or colorectal, lung, endometrial, or thyroid cancer.

This was a dose-finding study, and dosages of 5 mg daily to 60 mg daily were tested for the maximum-tolerated dose. Patients were given BGB-283 until disease progression.

Dr Jayesh Desai

Dr Desai presented data for 29 patients treated with BGB-283.

Of seven patients with BRAF V600E mutations, one with thyroid cancer and one with melanoma showed a confirmed partial response. Of 18 patients with KRAS mutations, one with endometrial cancer showed a confirmed partial response and one with non-small-cell lung cancer showed an unconfirmed partial response.

All partial responses were ongoing, with a response duration of more than 200 days at the time of data cutoff. However, the patient with endometrial cancer had a duration of response of 411 days and a progression-free survival of 455 days.

Dr Desai indicated that there were four dose-limiting toxicities with BGB-283 at doses of 40 mg or higher. Three patients experienced thrombocytopenia — two at the 40 mg dose and one at the 60 mg dose. Another patient experienced liver enzyme elevations at the 40 mg dose.

"Responses seen in three patients occurred early within two cycles of treatment. Moreover, the responses were sustained," concluded Dr Desai.

What's Next in the Development of BGB-283

Dr Desai explained that treating RAS tumors has been challenging, and these encouraging data need to be confirmed in a larger, more homogeneous patient population. In addition, emerging evidence suggests that signaling pathways driving proliferation and survival may differ across RAS mutations and tumor types.

None of the three patients with NRAS mutations in their tumors responded to therapy with BGB-283. "Despite these patients being selected by their underlying RAF or RAS mutation, these are preliminary results only with small numbers, and a very heterogeneous population in terms of tumor type. The underlying tumor type remains very important when trying to understand the context of an individual RAF, and perhaps even more, RAS mutation," Dr Desai told Medscape Medical News.

"In the context of RAS mutations, it will be important to determine which patients may most benefit from therapy with BGB-283," he said.

The next step for Dr Desai and his colleagues is to test the efficacy of BGB-283 in a phase 1b study of approximately 100 patients. The larger study will have a more homogeneous population, and patients will receive 30 mg once daily until disease progression.

The 30 mg dose was defined from the current study. Dr Desai told Medscape Medical News that in the current study, two patients showed dose-limiting toxicity — one with the 60 mg dose and one with the 50 mg dose.

"Although 40 mg once daily was defined as the maximum tolerated dose, we have reason to believe that the 30 mg dose is in the efficacious range and with less toxicity than the 40 mg dose," he said.

In his discussion of the study, Udai Banerji, MD, PhD, from the Institute of Cancer Research and The Royal Marsden Hospital in London, United Kingdom, noted that the half-life reported for BGB-283 is 110 days, so he questioned the daily dosing schedule and suggested that intermittent dosing might improve tolerability.

"Since responses were seen in a biomarker-stratified population, it is important to know if the target was hit. There was no evidence of this from the pharmacodynamics of the study," he added.

The study was funded by BeiGene. Dr Desai has disclosed no relevant financial relationships.

American Association for Cancer Research (AACR) 2016 Annual Meeting. Abstract CT005. ¨Presented April 17, 2016.

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