NEW YORK – In a new study published in the Journal of Clinical Oncology last week, researchers reported that in a Phase I trial, BeiGene's experimental RAF family kinase inhibitor lifirafenib (BGB-283) demonstrated promising activity in patients with KRAS-mutated non-small cell lung cancer and BRAF-mutated melanoma, thyroid cancer, and ovarian cancer.
Based on the preliminary safety and efficacy profile of the drug, researchers led by Jayesh Desai of the Royal Melbourne Hospital in Australia wrote that further studies should be done exploring the activity of lifirafenib alone or in combination with another drug for patients with RAS-mutated cancers who have developed resistance to a first-generation BRAF inhibitor.
Lifirafenib reversibly inhibits BRAF V600E, wild-type ARAF, BRAF, CRAF, and EGFR. The aim in the open-label, dose escalation study was to evaluate the safety and tolerability of the drug in cancer patients harboring BRAF and KRAS/NRAS mutations.
KRAS mutations are common in pancreatic, colorectal, lung, and biliary tract tumors. They also occur in 15 percent to 30 percent of endometrioid carcinomas. NRAS mutations are frequently detected in melanomas.
BRAF mutations occur in approximately 50 percent of malignant melanomas, 40 percent of thyroid carcinomas, 2 percent to 38 percent of low-grade serous ovarian cancers (LGSOCs), and approximately 10 percent of metastatic colorectal cancers.
During the dose escalation phase, the investigators established the maximum tolerated dose at 40 mg/d, and based on the treatment-related adverse events in this portion of the trial, they found that on average lifirafenib is better tolerated at doses lower than 30 mg. Five patients, or 14.3 percent, experienced an adverse event that led to therapy discontinuation.
In the dose-expansion portion of the study, during which 96 patients received lifirafenib at 30 mg in 21-day cycles, adverse events led 19 patients to discontinue therapy. Four patients experienced adverse events that were considered unrelated to the drug itself that led to death.
During the dose escalation portion of the study, one patient with BRAF-mutated melanoma had a complete response at the dose of 40 mg/d. Eight patients out of 53 with BRAF-mutated tumors saw their tumors shrink. Of these, five patients had BRAF V600E/K-mutated melanoma (including one who previously progressed on a RAF inhibitor); two had BRAF V600E-mutated thyroid or papillary thyroid cancer; and one had BRAF V600E-mutated low-grade serous ovarian cancer. One patient with BRAF-mutated non-small cell lung cancer had an unconfirmed partial response. A patient with KRAS-mutated endometrial cancer and a patient with KRAS codon 12-mutated NSCLC had confirmed partial responses. Of the patients with KRAS mutations, 32 patients or 54.2 percent had stable disease.
None of the 20 patients with KRAS/NRAS-mutated colorectal cancer responded to lifirafenib, but a dozen patients had stable disease.
Median duration of response was 31.7 months during the dose escalation portion and 11.7 months during the dose expansion portion of the study. Median duration of stable disease during dose expansion was 4.1 months. For 10 BRAF-mutated patients and five KRAS-mutated patients, the duration of treatment was greater than one year.
In addition to calling for further studies of lifirafenib in BRAF inhibitor-resistant cancers, Desai and colleagues also noted the need for more studies comparing the drug's effects with that of other first-generation BRAF inhibitors.
The authors noted that detailed genetic information for responders and non-responders beyond underlying BRAF and KRAS mutations was unavailable for most patients, and that "additional investigation may be needed to understand the underlying mechanism of response and resistance to this novel agent and to inform future treatment decisions and/or trial design."
BeiGene is also collaborating with SpringWorks Therapeutics on a Phase I/II study of lifirafenib in combination with a MEK inhibitor.