On April 17, 2023 BeiGene, Ltd. (NASDAQ: BGNE; HKEX: 06160; SSE: 688235), and SpringWorks Therapeutics, Inc. (NASDAQ: SWTX), reported that they will present updated clinical data from the Phase 1b trial of BeiGene’s RAF dimer inhibitor, lifirafenib, in combination with SpringWorks’ MEK inhibitor, mirdametinib, in patients with advanced or refractory solid tumors with RAS mutations, RAF mutations and other MAPK pathway aberrations (Press release, BeiGene, APR 17, 2023, View Source [SID1234630140]). The data are being presented today in an oral presentation at the American Association for Cancer Research (AACR) (Free AACR Whitepaper) Annual Meeting 2023, taking place in Orlando, Florida.
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This press release features multimedia. View the full release here: View Source
"The lifirafenib plus mirdametinib combination represents a novel targeted approach to treat solid tumors driven by RAS/RAF mutations, and other MAPK pathway aberrations. The early clinical data reported here demonstrate the potential of this vertical combination strategy in addressing the substantial unmet medical need represented by patients with tumors driven by these genetic alterations." said Lusong Luo, Ph.D. Senior Vice President, External Innovation at BeiGene. "We are very excited about our continued study of this combination with its advancement into dose expansion this year."
"We are pleased by the progress of our collaboration with BeiGene on the lifirafenib and mirdametinib combination," said Saqib Islam, CEO of SpringWorks. "We view vertical inhibition approaches, such as this novel combination, as a promising strategy to improve outcomes in biomarker-defined subgroups of patients that lack efficacious treatments for their cancers."
Oral Presentation at the AACR (Free AACR Whitepaper) Annual Meeting 2023:
Safety, pharmacokinetics, and antitumor activity findings from a phase 1b, open-label, dose-escalation and expansion study investigating RAF dimer inhibitor lifirafenib in combination with MEK inhibitor mirdametinib in patients with advanced or refractory solid tumors
Presenter: Benjamin Solomon, M.D., Peter MacCallum Cancer Centre, Melbourne, Australia
Session Title: Mini-symposium Session CTMS02 – Targeting the KRAS Pathway in the Clinic
Abstract #: CT033
Session Date and Time: Monday, April 17, 2023, 3:50-4:00 PM ET
This ongoing Phase 1b trial (NCT03905148) is an open-label, dose escalation and expansion study to investigate the safety, pharmacokinetics (PK) and antitumor activities of mirdametinib in combination with lifirafenib, BeiGene’s RAF dimer inhibitor, in patients with advanced or refractory solid tumors harboring RAS mutations, RAF mutations, and other MAPK pathway aberrations.
Results from the Part A dose-escalation and dose-finding study are being presented at AACR (Free AACR Whitepaper). This portion of the study was designed to evaluate the safety, tolerability, and pharmacokinetics of the combination, and determine the maximum tolerated dose and/or recommended Phase 2 dose.
As of the data cut-off of January 20, 2023, 71 patients were treated across 9 dose levels evaluating different dosing regimens. Results suggest that lifirafenib in combination with mirdametinib demonstrated a favorable safety profile, with low incidence of dose limiting toxicities and treatment-emergent adverse events that led to dose discontinuations. The most common treatment-related adverse events related to lifirafenib and/or mirdametinib (>15%) were dermatitis acneiform (42%), fatigue (32%), diarrhea (27%), platelet count decreased (18%), alopecia (18%), nausea (17%) and alanine aminotransferase increased (16%).
The combination showed antitumor activity in patients with various KRAS, NRAS, and BRAF mutations across several solid tumor types, including low-grade serous ovarian cancer (LGSOC), non-small cell lung cancer (NSCLC), and endometrial cancer. Among 62 efficacy-evaluable patients, 14 patients (23%) had confirmed objective responses. Of 17 patients with LGSOC treated, 10 patients (59%) had objective responses, with median duration of treatment of approximately 26 months. Of the 4 endometrial cancer patients treated, 2 (50%) had objective responses in tumors that harbor BRAF fusion mutation or KRAS mutation, respectively. Of the 11 patients with NSCLC treated, 2 (18%) had objective responses in tumors that harbor NRAS mutation or BRAF V600E mutation, respectively. These data support the advancement of this combination into the dose-expansion portion of the study, which will focus on a biomarker selected patient population with a tumor agnostic approach. The expansion is expected to start in the second half of 2023.
"Our findings indicate that the combination of lifirafenib and mirdametinib treatment demonstrated antitumor activity in patients with various KRAS, NRAS, and BRAF mutations across several solid tumor types known to be driven by the MAPK pathway and for which current treatment options are limited," said Benjamin Solomon, MBBS, PhD, FRACP, medical oncologist at Peter MacCallum Cancer Centre in Melbourne, Australia. "We are pleased with the risk-benefit profile seen to date with this combination and look forward to the further clinical investigation in the dose-expansion portion of the study."
About Lifirafenib
Lifirafenib (BGB-283) is an investigational novel small molecule designed to inhibit both monomeric and dimeric RAF kinase. Lifirafenib has demonstrated antitumor activity in preclinical models and in cancer patients with tumors harboring BRAF V600E mutations and non-V600E BRAF mutations, in which the monomeric form of RAF is implicated, as well as KRAS/NRAS mutations, in which the dimeric form of RAF is implicated.
About Mirdametinib
Mirdametinib is an investigational, oral, allosteric small molecule MEK inhibitor. Mirdametinib is designed to inhibit MEK1 and MEK2, which occupy pivotal positions in the MAPK pathway. The MAPK pathway is a key signaling network that regulates cell growth and survival and that plays a central role in multiple oncology and rare disease indications when genetically altered.
Mirdametinib is in development as a monotherapy treatment for neurofibromatosis type 1-associated plexiform neurofibromas (NF1-PN) and low-grade glioma (LGG), and as a combination therapy for the treatment of several subsets of biomarker-defined metastatic solid tumors. To date, over 300 subjects have been exposed to treatment with mirdametinib across clinical trials, with preliminary evidence of clinical activity against tumors driven by over-activated MAPK signaling.
The U.S. Food and Drug Administration (FDA) and the European Commission granted Orphan Drug designation for mirdametinib for the treatment of NF1, and the FDA granted Fast Track designation for the treatment of patients ≥ 2 years of age with NF1-PN that are progressing or causing significant morbidity.