On April 17, 2023 Cellectis (the "Company") (Euronext Growth: ALCLS – NASDAQ: CLLS), a clinical-stage biotechnology company using its pioneering gene-editing platform to develop life-saving cell and gene therapies, reported preclinical data on TALEN-edited MUC1 CAR T-cells at the American Association for Cancer Research (AACR) (Free AACR Whitepaper) Annual Meeting 2023 (Press release, Cellectis, APR 17, 2023, View Source [SID1234630145]). The data showed the capability of armored allogeneic MUC1 CAR T-cells to excel in the immune suppressive tumor micro-environment suggesting that they could be an effective option in treating relapsed and refractory triple negative breast cancer (TNBC) patients with limited therapeutic options.

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Tumor-associated MUC1 antigen is overexpressed in a large number of TNBC patients offering an effective discriminatory target for CAR T-cell therapy.

Cellectis’ MUC1 CAR T-cells are allogeneic and target Mucin 1 for TNBC and a variety of epithelial cancers. As other solid tumor targets can be plagued by safety concerns due to off-tumor expression, MUC1 is of high interest as its expression in normal epithelium is restricted to apical membranes. Additionally, MUC1 heavy glycosylation in normal tissue contrasts with Cellectis’ MUC1 CAR that is designed to recognize hypoglycosylated MUC1 present in cancer cells. Cellectis’ MUC1 CAR T-cells incorporate up to four TALEN-mediated knockouts and two knock-ins.

"We are very excited to share these encouraging preclinical data at AACR (Free AACR Whitepaper) that dissect how different attributes (knock-out or knock-in) contribute to the efficacy of our CAR T-cell product candidate" said Laurent Poirot, Ph.D., Senior Vice President Immunology at Cellectis. "We are convinced that allogeneic MUC1 CART-cells can be an effective option in the treatment of relapsed and refractory triple negative breast cancer."

The poster presentation at AACR (Free AACR Whitepaper) highlights the following preclinical data:

Intratumoral delivery of antigen-specific CAR T-cells resulted in effective control of tumor growth.
Results demonstrate superior activity of armored MUC1-CAR T-cells not only in tumor clearance but also in the recovery of normal glands.
Thus, innovative strategies can be used to allow CAR T-cell efficiency in the hostile tumor microenvironment while preserving safety.

Title: Deciphering the benefits of variable delivery routes and molecular armoring to enhance efficacy of MUC1-CAR T-cells in targeting triple-negative breast cancer

Session Title: Adoptive Cell Therapy 1

Presenter: Piril, Erler, Ph.D., Scientist II, Immuno-Oncology, Cellectis

Session Date and time: Sunday April 16, 2023, 1:30-5:00 PM ET
Location: Section 37
Poster Board Number: 14
Abstract Presentation Number: 899

On April 17, 2023 Candel Therapeutics, Inc. (Candel or the Company) (Nasdaq: CADL), a clinical stage biopharmaceutical company focused on developing and commercializing viral immunotherapies to help patients fight cancer, reported that the U.S. Food and Drug Administration (FDA) granted fast track designation for its lead asset CAN-2409, an investigational viral immunotherapy, plus valacyclovir in combination with pembrolizumab in order to improve survival or delay progression in patients with stage III/IV non-small cell lung cancer (NSCLC) who are resistant to first line PD-(L)1 inhibitor therapy and who do not have activating molecular driver mutations or have progressed on directed molecular therapy (Press release, Candel Therapeutics, APR 17, 2023, View Source [SID1234630144]). Fast track designation is a process designed to facilitate the development and expedite the review of medicines to treat serious conditions and fulfill an unmet medical need. An investigational medicine that receives fast track designation may be eligible for more frequent interactions with the FDA to discuss the candidate’s development plan and, if relevant criteria are met, eligibility for accelerated approval and priority review.

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"We are pleased with the FDA’s decision to grant fast track designation for CAN-2409, which reinforces our belief that our investigational medicine has meaningful potential to treat those living with late-stage lung cancer," said Paul Peter Tak, MD, PhD, FMedSci, President and CEO of Candel. "Despite progress made in recent years, there remains a significant unmet need for patients with lung cancer who have an inadequate response to standard of care immune checkpoint inhibitors. Fast track designation is intended to bring promising medicines to patients sooner and the receipt of this designation by the FDA reinforces our belief that CAN-2409 has the potential to improve outcomes for patients who lack other treatment options."

CAN-2409 is an investigational viral immunotherapy designed to stimulate an individualized, systemic immune response to the patient’s specific tumor. CAN-2409 plus valacyclovir in combination with continued PD-1/PD-L1 agents is being evaluated in an ongoing, open-label phase 2 clinical trial (NCT04495153) in patients with late-stage NSCLC.

During its R&D Day in December 2022, the Company reported data from 26 patients with NSCLC in its ongoing phase 2 clinical trial demonstrating evidence of local and systemic anti-tumor activity and showed a disease control rate of 77 percent (20/26) in patients entering the trial with disease progression despite previous immune checkpoint inhibitor treatment. Importantly, CAN-2409 demonstrated a favorable change in the trajectory of tumor growth in all patients for whom pre-enrollment scans were available as of October 21, 2022.

The Company expects to present updated clinical data from its phase 2 clinical trial in the third quarter of 2023.

On April 17, 2023 Black Diamond Therapeutics, Inc. (Nasdaq: BDTX), a clinical-stage precision oncology medicine company developing MasterKey therapies designed to overcome limitations of existing therapies by targeting families of oncogenic driver mutations in patients with genetically defined cancers, reported the presentation of three posters highlighting the design of the phase 1 clinical study of BDTX-1535 and new preclinical data on BDTX-1535 and BDTX-4933 at the 2023 American Association of Cancer Research (AACR) (Free AACR Whitepaper) Annual Meeting being held in Orlando, Florida (Press release, Black Diamond Therapeutics, APR 17, 2023, View Source [SID1234630143]).

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"Black Diamond’s MasterKey approach to precision oncology medicines is grounded in our deep understanding of the characterization of oncogenic mutations, and these presentations highlight the depth of our work to expand the addressable patient population for precision oncology. With an everchanging treatment landscape for genetically defined cancers, we believe that our approach to grouping our targets into druggable oncogene families presents a truly differentiated opportunity to address the continuing unmet need of patients," said Elizabeth Buck, Ph.D., Chief Scientific Officer of Black Diamond. "Our MAP Drug Discovery Engine has enabled us to intricately design MasterKey inhibitors based on extensive preclinical and real-world data, elucidating what we believe to be the necessary attributes for effectively targeting shared, activated conformations used by oncogenic drivers for tumor growth. Our fourth-generation irreversible brain penetrant EGFR MasterKey inhibitor, BDTX-1535, has demonstrated its ability to achieve potent anti-tumor activity against EGFR alterations and amplifications in a broad range of preclinical NSCLC and GBM models and we look forward to continuing to advance its development in the clinic and providing a first clinical update in the second half of this year. Our next most advanced program, BDTX-4933 was designed to be brain penetrant and selectively inhibits aberrant RAF signaling as result of BRAF class I, II, III and RAS oncogenic mutations without inducing paradoxical activation. We are encouraged by the results shared today, which support its potentially best-in-class profile."

BDTX-1535 Program:

Black Diamond presented two posters highlighting BDTX-1535’s preclinical development as well as the ongoing Phase 1 study.

In a poster titled, "Discovery of BDTX-1535, a novel brain penetrant, irreversible, potent, wild type sparing EGFR MasterKey inhibitor that targets oncogenic kinase domain mutations as well as extracellular domain alterations for the treatment of NSCLC and GBM," Black Diamond outlined the unmet need for next generation EGFR inhibitors that target classical driver mutations as well as acquired and intrinsic resistance mutations expressed in the context of EGFR driver mutations in non-small cell lung cancer (NSCLC), and EGFR alterations expressed in glioblastoma multiforme (GBM). Additional highlights include:

While EGFR C797S substitution is a frequently reported post-osimertinib resistance mutation, real world evidence indicates the emergence of other EGFR alterations that lead to resistance to osimertinib including EGFR kinase domain mutations (e.g., S768I), extracellular domain alterations (e.g., EGFRvIII, A289X), and EGFR amplification.
A family of extracellular domain EGFR alterations occurs in nearly 50% of GBM patients and these alterations are clinically resistant to all current generation inhibitors.
Real world data in GBM demonstrates EGFR alterations often co-occur and persist throughout treatment with current standard of care therapy. Black Diamond observed that the oncogenic isoform of EGFR in GBM is a covalent homo-dimer which can be formed and paradoxically activated by the binding of reversible EGFR inhibitors.
Black Diamond concluded that an effective EGFR inhibitor should meet four design principles and be: 1) potent and selective against a broad family of intracellular, extracellular EGFR oncogenic alterations and amplification, 2) wild type EGFR sparing, 3) irreversible to avoid paradoxical activation, and 4) central nervous system (CNS) penetrant.
In a poster titled, "A Phase 1 Study to Assess BDTX-1535, an Oral EGFR Inhibitor, in Patients with Glioblastoma or Non-Small Cell Lung Cancer," Black Diamond outlined its ongoing Phase 1, open-label, multicenter study to assess the safety, tolerability, pharmacokinetics, CNS penetrance and preliminary antitumor activity of BDTX-1535 in recurrent GBM (rGBM) or locally advanced or metastatic NSCLC with or without CNS disease. Key highlights include:

The monotherapy dose escalation portion will evaluate BDTX-1535 in patients with either rGBM expressing EGFR alterations or locally advanced/metastatic NSCLC harboring sensitizing EGFR mutations with or without CNS disease.
Patients with rGBM must have previously received available standard therapy of surgical resection followed by chemoradiotherapy and/or temozolomide (TMZ). Eligible NSCLC patients must have EGFR mutated NSCLC that has progressed following standard of care EGFR inhibitor therapy.
Following the establishment of a provisional recommended Phase 2 dose, BDTX-1535 monotherapy will be explored in the following dose expansion cohorts to further evaluate safety, pharmacokinetics (PK), and preliminary assessment of efficacy: 1) rGBM with confirmed EGFR alterations, 2) NSCLC with uncommon EGFR mutations following EGFR inhibitor therapy, and 3) NSCLC with acquired EGFR resistance mutation(s) following a 3rd generation EGFR inhibitor in the first-line setting. NSCLC patients may enroll with or without CNS metastases and must not be known to express excluded resistance mutations such as EGFR T790M or MET.
BDTX-1535 will also be studied in combination with TMZ to assess safety, tolerability, and a recommended combination dose for the treatment of patients with rGBM harboring EGFR mutations or variants.
Enrollment was initiated in 2022 and dose escalation is ongoing. Dose Expansion cohorts are expected to open in 2023.
Black Diamond remains on track to provide a clinical update on BDTX-1535 in the second half of 2023.

BDTX-4933 Program:

In a poster titled, "Preclinical characterization of a brain penetrant RAF inhibitor, BDTX-4933, targeting oncogenic BRAF Class I/II/III and RAS mutation," Black Diamond outlined its approach to characterizing BRAF, RAS and MAPK pathway in addition to the design and preclinical development of BDTX-4933:

Mutations in BRAF and RAS are often oncogenic and lead to a constitutively active MAPK pathway that promotes aberrant cell proliferation and tumor growth.
BDTX-4933 is a potent, reversible, CNS penetrant RAF MasterKey inhibitor designed to target a large family of oncogenic BRAF class I, II, III and RAS mutants.
In a panel of cancer cell lines that endogenously express BRAF or RAS mutations, BDTX-4933 demonstrated inhibition of the MAPK pathway signaling without paradoxical activation, resulting in potent inhibition of cellular proliferation.
In tumor models in vivo, BDTX-4933 showed target engagement, inhibiting ERK phosphorylation, achieving strong anti-tumor activity and tumor regression across tumor models driven by either BRAF or RAS mutations.
BDTX-4933 exhibits high CNS exposure leading to dose-dependent tumor growth inhibition, and survival benefit in an intracranial tumor model harboring oncogenic BRAF mutation.
Based on preclinical data, BDTX-4933 has a potential best-in-class profile to treat cancer patients harboring oncogenic BRAF Class I, II, III and RAS mutations, with or without brain disease.
Black Diamond expects to initiate a Phase 1 clinical trial of BDTX-4933 in patients with tumors harboring all-class BRAF or RAS mutations in the second quarter of 2023.

The posters from the AACR (Free AACR Whitepaper) Annual Meeting are available on the "Scientific Presentations and Publications" section of the Black Diamond Therapeutics website.

On April 17, 2023 MapKure, LLC, 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 1a/1b study of BGB-3245, an investigational, selective RAF dimer inhibitor, in adult patients with advanced or refractory solid tumors harboring MAPK pathway aberrations (Press release, BeiGene, APR 17, 2023, View Source [SID1234630141]). 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 promising data we are sharing at AACR (Free AACR Whitepaper) demonstrate the value of our next-generation RAF dimer inhibitor, BGB-3245, as a monotherapy in patients with MAPK pathway-altered cancers, especially its potential to address key primary and resistance gene alterations that are currently unaddressed by approved therapies," said Lusong Luo, Ph.D., Acting CEO of MapKure and Senior Vice President, External Innovation at BeiGene. "We believe that our early clinical data supported the advancement into our selected expansion cohorts which are now underway."

"SpringWorks is committed to developing genomically-targeted therapies for patients with cancer and our MAPK directed portfolio is a cornerstone of our efforts. In particular, we are encouraged by the promising activity BGB-3245 is showing in patients with MAPK pathway aberrations," said Saqib Islam, CEO of SpringWorks. "We and our partners are excited by the advancement of this program and are eager to continue making strides to benefit patients in significant need of new therapeutic options."

Oral Presentation at the 2023 AACR (Free AACR Whitepaper) Annual Meeting:

A first-in-human, phase 1a/1b, open-label, dose-escalation and expansion study to investigate the safety, pharmacokinetics, and antitumor activity of the RAF dimer inhibitor BGB-3245 in patients with advanced or refractory tumors

Presenter: Alison M. Schram, M.D., Memorial Sloan Kettering Cancer Center in New York
Session Title: Mini-symposium Session CTMS02 – Targeting the KRAS Pathway in the Clinic
Abstract #: CT031
Session Date and Time: Monday, April 17, 2023, from 3:20-3:30 PM ET

This ongoing Phase 1a/1b trial (NCT04249843) is an open-label, dose escalation and expansion study of BGB-3245 in adult patients with advanced or refractory solid tumors harboring MAPK pathway alterations. Results from the Phase 1a 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, pharmacokinetics, preliminary antitumor activity of BGB-3245, and to determine its maximum tolerated dose and/or recommended Phase 2 dose to be used in select expansion cohorts.

As of the data cut-off of September 1, 2022, 42 patients were treated across six dose levels (5-60 mg daily). Patients were heavily pre-treated, having received a median three prior lines of therapy (range 1-9), including standard of care immunotherapy and targeted therapy regimens. Results demonstrated that BGB-3245 had a manageable safety profile, with adverse event findings consistent with other MAPK pathway inhibitors. The most common treatment-related adverse events (>15%) were rash acneiform (33%), rash maculopapular (24%), and fever (17%). The 40 mg once daily dose was determined to be the maximum tolerated dose of BGB-3245. In addition, encouraging anti-tumor activity was observed in heavily pretreated patients, with an objective response rate of 18% (6 confirmed responses including one complete response in 33 efficacy evaluable patients). The disease control rate was 79% and clinical benefit rate was 42%. Objective responders include patients with tumors harboring BRAF V600E that had progressed on prior BRAF/MEK inhibitors with or without checkpoint inhibitor treatment, BRAF Class II mutation, BRAF fusion, NRAS and KRAS mutations. Median time on treatment was approximately 5 months (range: 1.9-23.6 months) and 9 patients remain on treatment. These data supported the advancement of BGB-3245 into the Phase 1b dose expansion portion of the study, which has been enrolling patients since October 2022 in defined cohorts.

"These data support the ongoing investigation of BGB-3245 in defined cohorts, including BRAF V600 tumors that have progressed after prior BRAF and/or MEK inhibitor treatment, solid tumors with BRAF class II mutations and BRAF fusions, and NRAS mutant melanoma," said Alison M. Schram, M.D., Assistant Attending Physician at Memorial Sloan Kettering Cancer Center in New York. "These patients have very limited treatment options and I look forward to the further development of BGB-3245 as it continues to advance through the dose expansion cohorts."

About BGB-3245

BGB-3245 is an investigational, oral, selective small molecule inhibitor of RAF monomer and dimer forms. Preclinical data demonstrate that BGB-3245 has activity in tumor models that have BRAF/MEK inhibitor-resistance mutations, suggesting BGB-3245 could provide a therapeutic option for patients who have progressed on prior BRAF and/or MEK inhibitions. In addition, BGB-3245 has shown activity in preclinical models that have BRAF class II/III mutations, fusions, and splice isoforms, for which approved BRAF inhibitors are ineffective. These mutations and fusions have been identified in several solid tumors to be drivers of cancer growth, including in melanoma, non-small cell lung cancer, colorectal cancer, thyroid cancer, and other cancers.

In addition to its development as a monotherapy in several genetically defined solid tumor types, a Phase 1/2a combination study of BGB-3245 and mirdametinib is ongoing (NCT05580770) and BGB-3245 also has the potential to be used in rational combination therapies in the future.

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.