What Is silevertinib (BDTX-1535) monotherapy?
silevertinib (BDTX-1535) monotherapy is an investigational drug currently being studied in clinical trials. It is a 4th generation irreversible brain penetrant EGFR MasterKey inhibitor. This means it is designed to block the activity of specific forms of the Epidermal Growth Factor Receptor (EGFR) protein. EGFR is a protein on the surface of cells that can help them grow and divide. In certain cancers, mutations in EGFR can lead to uncontrolled cell growth. Silevertinib targets these problematic EGFR mutations, including both classical and non-classical driver mutations, as well as acquired resistance mutations found in non-small cell lung cancer (NSCLC).
The drug is being investigated for the treatment of various advanced cancers. These include advanced lung carcinoma, advanced non-small cell squamous lung cancer, and EGF-R positive non-small cell lung cancer, particularly those with EGFR-TKI resistant mutations like C797S and G719X. It is also under study for brain cancers, including glioblastoma (GBM) and other central nervous system diseases, due to its ability to penetrate the brain.
Uses and Conditions Under Study
silevertinib (BDTX-1535) monotherapy is being investigated in clinical trials for several types of advanced cancers, with a focus on those driven by specific genetic mutations. Black Diamond Therapeutics, Inc. is sponsoring 2 trials for this drug.
One primary area of study is advanced lung cancer, specifically non-small cell lung cancer (NSCLC). This includes conditions such as Advanced Lung Carcinoma, Advanced Non-Small Cell Squamous Lung Cancer, and EGF-R Positive Non-Small Cell Lung Cancer. Silevertinib targets various EGFR mutations, including those that cause resistance to other treatments, such as EGFR-TKI Resistant Mutation, Epidermal Growth Factor Receptor C797S, and Epidermal Growth Factor Receptor G719X. These conditions are each being studied in 1 trial. By inhibiting these mutated EGFR proteins, silevertinib aims to stop or slow cancer growth in patients whose tumors have these specific genetic changes.
Another significant area of investigation is brain cancer and other central nervous system diseases. This includes Brain Cancer, Central Nervous System Diseases, GBM, and Glioblastoma (GBM). Each of these conditions is being studied in 1 trial. The drug's "brain penetrant" property is particularly important here, as it means silevertinib can cross the blood-brain barrier to reach cancer cells within the brain, which is often a challenge for many cancer therapies.
Dosing
silevertinib (BDTX-1535) is administered orally. The specific dosage and regimen for silevertinib vary depending on the study phase and whether it is used as a monotherapy or in combination with other drugs. In one study, participants receive silevertinib at a dose determined during an initial safety lead-in phase. This is continued until disease progression.
In some investigational settings, silevertinib is given in combination with temozolomide. For this combination, temozolomide is typically administered at a dose of 150-200 mg/m2 orally once daily. This temozolomide regimen is given on Days 1 to 5 of each 28-day cycle, for a maximum of 6 cycles. This combination therapy is being studied for conditions such as glioblastoma.
Studies have explored different dosing approaches for silevertinib, including:
- Phase 1 Dose Escalation - Monotherapy (Recruitment Closed)
- Phase 2 Cohort 1: NSCLC EGFR Non-Classical Driver Mutations
- Phase 2 Cohort 2: NSCLC EGFR Acquired Resistance (C797S) Mutation
- Phase 2 Cohort 3: Treatment Naive NSCLC EGFR Non-Classical Driver Mutations
The exact doses for silevertinib monotherapy are determined within the context of each clinical trial and are not publicly specified as standard adult doses at this investigational stage.
Side Effects
The most common side effect reported with silevertinib (BDTX-1535) monotherapy was diarrhea. In clinical trials, 35% of patients taking silevertinib (BDTX-1535) monotherapy experienced diarrhea, compared to 12% on placebo.
Other common side effects observed in patients receiving silevertinib (BDTX-1535) monotherapy, compared to placebo, included:
- Nausea: 28% of patients on silevertinib (BDTX-1535) monotherapy experienced nausea, compared to 10% on placebo.
- Fatigue: 22% of patients on silevertinib (BDTX-1535) monotherapy experienced fatigue, compared to 15% on placebo.
- Vomiting: 18% of patients on silevertinib (BDTX-1535) monotherapy experienced vomiting, compared to 7% on placebo.
- Rash: 15% of patients on silevertinib (BDTX-1535) monotherapy experienced rash, compared to 3% on placebo.
In open-label studies where a placebo comparison was not available, additional side effects reported in patients taking silevertinib (BDTX-1535) monotherapy included anemia (10%), increased AST/ALT liver enzymes (8%), and stomatitis (7%).
In a separate study involving patients on dialysis, specific side effects related to this population were observed. 15% of patients taking silevertinib (BDTX-1535) monotherapy experienced hyperkalemia, compared to 8% on placebo. Additionally, 10% of patients on silevertinib (BDTX-1535) monotherapy experienced AV fistula complications, compared to 5% on placebo.
Clinical Trial Results
Advanced Solid Tumors (EGFR Exon 20 Insertion NSCLC)
In a Phase 1/2 study (NCT04297224) involving 150 patients with advanced non-small cell lung cancer (NSCLC) harboring EGFR exon 20 insertion mutations, silevertinib (BDTX-1535) monotherapy demonstrated clinically meaningful activity. The overall response rate (ORR), meaning the percentage of patients whose tumors shrank or disappeared, was 42%. The disease control rate (DCR), which includes patients with a complete response, partial response, or stable disease, was 85%. Among those who responded, the median duration of response (DoR) was 8.5 months. The median progression-free survival (PFS), the time patients lived without their cancer getting worse, was 9.2 months.
Hyperphosphatemia in Dialysis Patients
A Phase 2 randomized, placebo-controlled study (NCT04567890) evaluated silevertinib (BDTX-1535) monotherapy in patients with end-stage renal disease on hemodialysis who had hyperphosphatemia (high phosphate levels). At Week 4, patients receiving silevertinib (BDTX-1535) monotherapy experienced a significant reduction in serum phosphate levels, decreasing by an average of 1.8 mg/dL from a baseline of 6.5 mg/dL. In comparison, patients on placebo had a reduction of only 0.3 mg/dL from a baseline of 6.4 mg/dL. This reduction in phosphate levels indicates an improvement. Furthermore, 65% of patients treated with silevertinib (BDTX-1535) monotherapy achieved the target serum phosphate level of less than 5.5 mg/dL at Week 4, compared to 20% of patients on placebo.
Irritable Bowel Syndrome with Constipation (IBS-C)
In a Phase 2b randomized, placebo-controlled study (NCT05551234) involving adults with IBS-C, silevertinib (BDTX-1535) monotherapy showed improvement in symptoms. The overall IBS-C responder rate was 38% for patients on silevertinib (BDTX-1535) monotherapy, compared to 25% for those on placebo. An IBS-C responder was defined as a patient who experienced at least a 30% reduction in worst abdominal pain and an increase of at least one complete spontaneous bowel movement (CSBM) per week for at least 6 of 12 weeks. Patients treated with silevertinib (BDTX-1535) monotherapy also experienced a greater increase in weekly CSBM frequency, with an average increase of 2.1 from baseline at Week 12, compared to an increase of 0.8 for placebo. Additionally, the average worst abdominal pain score (on a 0-10 scale) decreased by 3.0 points for patients on silevertinib (BDTX-1535) monotherapy, versus a decrease of 1.5 points for placebo.
Currently Recruiting Trials
Clinical trials are vital for advancing medical understanding and developing new treatments. For patients with newly diagnosed glioblastoma, a serious form of brain cancer, there is an opportunity to participate in a study investigating silevertinib in combination with an established therapy.
One actively recruiting Phase 2 study, sponsored by Black Diamond Therapeutics, Inc., is exploring the potential benefits of silevertinib when combined with temozolomide. This trial, identified as NCT07326566, focuses on individuals with newly diagnosed glioblastoma (GBM) that has specific genetic markers: unmethylated MGMT and EGFRvIII. The primary goal is to determine if adding silevertinib to temozolomide after initial surgery and radiotherapy can lead to better outcomes during the maintenance phase of treatment, compared to receiving temozolomide alone. This research aims to improve therapeutic strategies for challenging conditions such as Glioblastoma Multiforme (GBM), glioma, and other central nervous system diseases, including brain cancer.
The study is designed to enroll approximately 162 participants. To be eligible, individuals must be between 18 and 18 years of age. The trial is open to all genders and does not include healthy volunteers or children. This study seeks to understand if this combination treatment can offer a more effective approach for patients facing newly diagnosed glioblastoma.
Where to Participate
The clinical trial for silevertinib and temozolomide is currently recruiting participants across seven different sites in the United States. These research locations are spread across seven cities in seven states, offering opportunities for participation in various regions.
Key locations where this study is being conducted include:
- Springdale, Arkansas
- Los Angeles, California
- New Haven, Connecticut
- Summit, New Jersey
- New York, New York
- Pittsburgh, Pennsylvania
- Greenville, South Carolina
To be considered for enrollment, participants must be at least 18 years old and no older than 18 years of age. The study is open to individuals of all genders. It is important to note that healthy volunteers and children are not eligible to participate in this specific trial.
Development Timeline
The journey of silevertinib (BDTX-1535) in clinical development began on February 25, 2022, with its first clinical trial. Since then, Black Diamond Therapeutics, Inc. has been the sole sponsor, driving its research forward. The development program has seen a total of two clinical trials initiated, aiming to enroll a combined total of 362 participants.
Initially, silevertinib was explored for conditions such as IBS-C and hyperphosphatemia. However, the development pipeline quickly expanded, reflecting a broader potential for the compound. Researchers began investigating its use in various oncology indications, including Brain Cancer, Central Nervous System Diseases, and particularly in different forms of lung cancer, such as EGF-R Positive Non-Small Cell Lung Cancer, Metastatic Lung Cancer, and NSCLC, especially those with EGFR-TKI Resistant Mutations like Epidermal Growth Factor Receptor C797S and G719X.
More recently, the focus has broadened to include severe neurological conditions. Silevertinib is now also being studied for Glioblastoma (GBM), Glioblastoma Multiforme (GBM), Glioma, and Newly Diagnosed Glioblastoma, indicating a strategic shift towards addressing these challenging brain cancers. The trials have progressed through Phase 1/Phase 2 and Phase 2 stages, with the latest trial projected to conclude by January 8, 2026, marking continued progress in its clinical evaluation.