Dabrafenib

ATP-Competitive Binding to Active Conformation of BRAF Kinase

This compound binds to the active conformation of BRAF kinase in an ATP-competitive manner. nih.govnih.gov This competitive binding prevents ATP from accessing the active site, thereby inhibiting the phosphorylation activity of BRAF. Studies have demonstrated that this compound can displace known ATP-competitive ligands from both wild-type and BRAF V600E, indicating its interaction with the ATP-binding site. nih.gov

Target Specificity for BRAF V600 Mutants

While this compound can inhibit wild-type BRAF, it exhibits a significantly higher affinity and potency for mutant forms of BRAF, particularly those with the V600 mutation. drugbank.comstemcell.com This includes BRAF V600E, BRAF V600K, and BRAF V600D mutations. drugbank.comnih.gov Preclinical studies have shown that this compound is highly potent against cell lines harboring the BRAF V600E mutation, with reported IC50 values in the low nanomolar range. plos.orgstemcell.com It also demonstrates inhibitory effects on cell lines with other V600 mutations like V600K and V600D. nih.gov This selective targeting of mutated BRAF is crucial for its therapeutic effect in cancers driven by these specific alterations. drugbank.comresearchgate.net

Comparative Selectivity Profile (e.g., vs. Vemurafenib)

This compound has been shown to have a distinct selectivity profile compared to other BRAF inhibitors like vemurafenib. Studies suggest that this compound is a more selective inhibitor of BRAF with less potency for CRAF (another RAF protein) than vemurafenib. nih.govresearchgate.net This difference in selectivity may contribute to variations in their off-target effects and clinical profiles. life-science-alliance.orgresearchgate.net While both inhibit mutant BRAF, their interactions with other kinases, including wild-type BRAF and CRAF, can differ. life-science-alliance.orgnih.gov

Decreased MEK and ERK Phosphorylation

A primary consequence of BRAF inhibition by this compound is the decreased phosphorylation of MEK and subsequently ERK. plos.orgdovepress.comnih.gov In BRAF V600E mutant cells, this compound inhibits MEK and ERK activation in a concentration-dependent manner. plos.orgnih.gov This reduction in phosphorylation reflects the disruption of the constitutively active signaling cascade initiated by the mutated BRAF. Data from preclinical studies in BRAF V600E cell lines demonstrate this effect. plos.orgnih.gov

Note: This table is illustrative based on findings indicating concentration-dependent inhibition of pMEK and pERK in BRAF V600E cells. plos.orgnih.gov

Paradoxically, in cells with wild-type BRAF but activating mutations in RAS, BRAF inhibitors like this compound can lead to increased MAPK pathway activation through CRAF signaling. nih.govplos.orgnih.govmdpi.com However, this paradoxical activation can be abrogated by combining this compound with a MEK inhibitor. plos.orgnih.govnih.govaacrjournals.org

Cellular Effects of MAPK Pathway Abrogation

The abrogation of downstream MAPK signaling through this compound-mediated BRAF inhibition results in several cellular effects in sensitive cancer cells. These include decreased cell proliferation, induction of cell cycle arrest, and activation of apoptosis (programmed cell death). nih.govplos.orgnih.gov

In BRAF V600E mutant cell lines, this compound treatment has been shown to inhibit cell proliferation and induce cell cycle arrest at the G1 phase. plos.orgnih.gov This is followed by the activation of caspases-3/7, key executioners of apoptosis. nih.govnih.gov Preclinical data in xenograft models using BRAF V600E human melanoma cell lines confirm that oral administration of this compound inhibits ERK activation, reduces the proliferation marker Ki67, and increases the growth inhibition marker p27, leading to tumor growth inhibition. plos.orgnih.gov

Note: This table summarizes observed cellular effects and corresponding markers based on research findings. nih.govplos.orgdovepress.comnih.gov

The effectiveness of this compound is largely dependent on the presence of activating BRAF mutations, particularly at the V600 codon, which drive the aberrant MAPK signaling. drugbank.comdermnetnz.orgpathologytestsexplained.org.au

G1 Cell Cycle Arrest

In cells expressing the BRAFV600E mutation, this compound treatment leads to a decrease in MEK and ERK phosphorylation. nih.gov This inhibition of downstream MAPK signaling results in an initial arrest of the cell cycle at the G1 phase. nih.govplos.orgnih.gov Studies have shown that this compound arrests BRAFV600E cells at the G1 phase, while wild-type BRAF cells remain unaffected at comparable concentrations. plos.orgnih.gov The on-target mechanism for cell growth inhibition by this compound is supported by the observed downregulation of Ki67, a marker of cell proliferation, and upregulation of p27, a cell cycle inhibitor. plos.org

Induction of Apoptosis (Caspase-3/7 Activation)

Beyond cell cycle arrest, this compound also induces apoptosis in BRAFV600E mutant cells. nih.govplos.orgnih.gov This programmed cell death is mediated through the activation of effector caspases, specifically Caspase-3 and Caspase-7. nih.govplos.orgnih.govspandidos-publications.com The activation of these caspases leads to increased DNA fragmentation, a hallmark of apoptosis. plos.orgnih.gov While the extent of apoptosis can vary between cell lines, this compound has been consistently shown to induce Caspase-3/7 activation in BRAFV600E cells. nih.gov

RAS-Dependent Paradoxical Activation

Paradoxical activation of the MAPK pathway by BRAF inhibitors like this compound in wild-type BRAF cells is dependent on RAS activity. nih.govaacrjournals.orgresearchgate.net In cells with mutant RAS and wild-type RAF proteins, this compound can elevate phospho-MEK and phospho-ERK levels. researchgate.net This occurs because, in the presence of upstream RAS activity, BRAF inhibitors can induce the formation of RAF dimers. oncotarget.comnih.gov When a BRAF inhibitor binds to one protomer in a RAF dimer, it can allosterically activate the other protomer, leading to downstream ERK activation, even in the absence of a BRAF mutation. oncotarget.comnih.gov

CRAF-Dependent Signaling

Studies have demonstrated that the paradoxical MAPK pathway activation induced by this compound in wild-type RAF and mutant RAS cell lines is dependent on CRAF. plos.orgresearchgate.netresearchgate.net Depletion of CRAF using siRNA has been shown to reduce this paradoxical upregulation of MAPK signaling to baseline levels, whereas depletion of ARAF or BRAF did not have the same effect. plos.orgresearchgate.net This suggests that CRAF plays a crucial role in mediating the paradoxical activation observed with this compound in these cellular contexts. plos.orgresearchgate.net

Mechanistic Implications for Combination Therapy

The paradoxical activation of the MAPK pathway in BRAF wild-type cells highlights a rationale for combination therapy. Combining a BRAF inhibitor like this compound with a MEK inhibitor can abrogate this increased MAPK signaling. plos.orgnih.gov MEK inhibitors act further downstream in the MAPK pathway, effectively blocking the signal even if RAF is paradoxically activated. nih.gov This dual inhibition provides more potent and durable suppression of ERK signaling and can potentially mitigate the adverse effects associated with paradoxical activation, such as the induction of cutaneous squamous cell carcinomas. nih.govoncotarget.com Preclinical studies have shown that combining this compound with a MEK inhibitor like Trametinib results in enhanced tumor growth inhibition and improved pro-apoptotic effects compared to this compound monotherapy in certain cell lines. oncotarget.com

Inhibition of BRAF V600E Mutated Cell Lines (IC50 Values)

This compound has demonstrated potent inhibitory activity against cell lines carrying the BRAF V600E mutation. In biochemical assays, this compound was able to inhibit BRAF V600E with IC50 values reported to be less than 2 nM. fda.gov Specifically, one study indicated an IC50 of 0.65 nM for BRAF V600E kinase inhibition. fda.gov In cellular assays, this compound showed growth inhibition in the majority of tested cell lines carrying BRAF V600E mutations. fda.gov For instance, in A375 cells with BRAF V600E mutations, this compound treatment resulted in an IC50 of 9.5 µM. iiarjournals.org Another study using cell proliferation assays reported an IC50 of 200 nM for inhibiting BRAF V600E mutated cell lines. nih.gov Sixteen out of 20 cell lines encoding BRAF V600E were sensitive to this compound, with gIC50 values less than 200 nM in a 3-day proliferation assay. plos.orgnih.gov

Activity Against Other BRAF V600 Mutant Cell Lines (V600K, V600D, V600R)

Beyond the V600E mutation, this compound has also shown activity against other BRAF V600 mutant cell lines, including V600K, V600D, and V600R. nih.govresearchgate.netmdpi.com In biochemical assays, this compound inhibited BRAF V600K and BRAF V600D with IC50 values of 0.5 nM and 1.84 nM, respectively. fda.gov Studies have confirmed this compound's activity against V600K, V600D, and V600R mutations. researchgate.netmdpi.com For example, in a 3-day proliferation assay, three out of five other mutant BRAF cell lines, including WM-115 (BRAF V600D) and YUMAC (BRAF V600K), were sensitive to this compound with gIC50 values less than 30 nM. plos.orgnih.gov this compound demonstrated remarkable inhibition of cell proliferation in melanoma cell lines carrying BRAF V600D or BRAF V600R mutations. researchgate.netspringermedizin.denih.govnih.gov

Effects on Cell Proliferation and Viability in BRAF-Mutated Cells

This compound treatment leads to a decrease in cell viability and inhibits cell proliferation in BRAF-mutated cells. iiarjournals.orgnih.govmdpi.comnih.gov Cellular inhibition of BRAF V600E kinase activity by this compound results in decreased MEK and ERK phosphorylation and inhibition of cell proliferation. nih.gov This inhibition occurs through an initial G1 cell cycle arrest, followed by cell death. nih.gov this compound induced a decrease in cell viability, impeded cellular adhesion, inhibited cellular aggregation and spheroid formation, arrested the cell cycle in the G1 phase, and induced apoptosis in melanoma cells with the BRAF V600E mutation. iiarjournals.orgnih.gov In BRAF V600E cells, this compound inhibits MEK and ERK activation in a concentration-dependent manner. plos.org this compound strongly inhibited viability in BRAF-mutated anaplastic thyroid cancer cells by demonstrating G0/G1-arrest via the downregulation of MEK/ERK phosphorylation. spandidos-publications.com

Assessment of this compound on Wild-Type BRAF Cell Lines

In contrast to its effects on BRAF-mutated cells, this compound shows low inhibition of most cell lines with wild-type BRAF. fda.gov While this compound is a potent inhibitor of mutated BRAF, it also inhibits wild-type BRAF and CRAF at similar concentrations (≤ 5 nM) in biochemical assays. fda.gov However, in cellular assays, this compound showed low growth inhibition in most cells with wild-type BRAF. fda.gov Studies have shown that this compound can cause RAS-dependent paradoxical activation of the MAPK pathway in BRAF wild-type cells. nih.gov This paradoxical activation in wild-type RAF cells appears to be CRAF-dependent. plos.org this compound should not be used in patients with wild-type BRAF melanoma or wild-type BRAF NSCLC, as its efficacy and safety have not been established in these populations. europa.eu

Tumor Growth Inhibition in BRAF V600E Xenograft Models

In vivo experiments have confirmed that this compound inhibits tumor growth in BRAF V600E xenograft mouse models. fda.govnih.govnih.govresearchgate.netstemcell.com Preclinical data in xenograft mouse models confirm that this compound inhibits the MAPK pathway in BRAF V600 mutated melanoma cell lines, leading to decreased proliferation and regression. nih.govnih.gov this compound showed dose-dependent inhibition of tumor growth in a BRAF V600E (Colo 205) human tumor xenograft model after a 14-day treatment, with 4 out of 8 mice showing partial regressions at 100 mg/kg. nih.govresearchgate.net In a BRAF V600E-containing xenograft model of human melanoma, orally administered this compound inhibited ERK activation, downregulated Ki67, and upregulated p27, leading to tumor growth inhibition. nih.gov Immunohistochemical analysis of tumor markers 6 hours post-final dose of this compound demonstrated downregulation of ERK phosphorylation and Ki67 by 89% and 28%, respectively, as well as upregulation of the growth inhibition marker p27 by 54%. nih.govresearchgate.net

While sustained administration of this compound showed tumor growth inhibition, tumor re-growth was observed after a period, suggesting the development of a resistance mechanism upon constant drug exposure. nih.gov

Correlation of MAPK Signaling Inhibition with Tumor Growth Reduction

This compound, a potent and selective inhibitor of mutated BRAF kinase, has demonstrated a clear correlation between the inhibition of MAPK signaling and the reduction of tumor growth in preclinical models. In BRAFV600E-containing xenograft models of human melanoma, oral administration of this compound led to tumor growth inhibition. plos.orgresearchgate.netnih.govnih.govebi.ac.uk This inhibition of tumor growth was accompanied by a decrease in ERK activation. plos.orgnih.govnih.govebi.ac.uk The sustained reduction of phosphorylated ERK (pERK) levels for up to 18 hours post-dosing after multiple days of treatment supports an on-target mechanism for the observed cell growth inhibition by this compound. plos.orgnih.gov In vivo studies have further supported this correlation, showing that the inhibition of MAPK signaling directly correlated with decreased tumor cell growth, and dose-dependent tumor regression was observed with continuous drug exposure. plos.orgnih.gov

Modulation of Tumor Markers (e.g., ERK Phosphorylation, Ki67, p27)

Preclinical studies have shown that this compound modulates key tumor markers associated with cell proliferation and growth inhibition. In BRAFV600E-containing xenograft models, this compound inhibited ERK activation, leading to a downregulation of Ki67 and an upregulation of p27. plos.orgresearchgate.netnih.govnih.govebi.ac.uk Immunohistochemical analysis of tumors from treated animals revealed a significant downregulation of pERK and Ki67, markers of MAPK signaling and cell proliferation, respectively. plos.orgnih.gov Conversely, there was an observed upregulation of p27, a marker associated with cell cycle arrest and growth inhibition. plos.orgnih.gov Specifically, this compound treatment elicited an 89% downregulation of pERK, a 28% downregulation of Ki67, and a 54% upregulation of p27 in tumor samples. plos.orgnih.gov These changes in tumor markers are consistent with the observed tumor growth inhibition and support the on-target mechanism of this compound. plos.orgnih.gov

Abrogation of Paradoxical MAPK Activation with MEK Inhibitors

A significant observation in preclinical studies was the ability of this compound to induce MAPK pathway activation in wild-type BRAF cells, particularly those with mutant RAS. plos.orgresearchgate.netnih.govnih.govpnas.org This paradoxical activation is thought to contribute to the development of cutaneous squamous cell carcinomas and keratoacanthomas observed in patients treated with BRAF inhibitors. plos.orgresearchgate.netnih.govnih.govpnas.org Preclinical investigations demonstrated that the concomitant administration of BRAF and MEK inhibitors abrogated this paradoxical BRAF inhibitor-induced MAPK signaling in cells. plos.orgresearchgate.netnih.govnih.govebi.ac.uk This abrogation of paradoxical activation in wild-type RAF cells, which are dependent on the MAPK pathway for growth, highlighted the potential benefit of combining this compound with a MEK inhibitor. plos.orgnih.gov

Enhanced Tumor Growth Inhibition with BRAF/MEK Combination

Preclinical studies provided compelling evidence that combining this compound with a MEK inhibitor, such as trametinib, results in enhanced tumor growth inhibition compared to either agent alone. plos.orgresearchgate.netnih.govnih.govebi.ac.ukresearchgate.netdovepress.com In BRAFV600E tumor xenograft models, combined oral treatment with this compound and trametinib demonstrated superior inhibition of tumor growth. plos.orgnih.gov This enhanced efficacy was observed even when compared to a higher dose of this compound monotherapy that provided maximum bioavailable blood levels. plos.orgnih.gov The combination of BRAF and MEK inhibitors has been shown to induce greater cell killing and prolong the time to the development of resistance in BRAFV600E-mutant melanoma models compared to single-agent treatment. dovepress.com This synergistic effect on tumor growth inhibition provided a strong preclinical basis for the clinical evaluation of this compound in combination with MEK inhibitors. plos.orgresearchgate.netnih.govnih.govebi.ac.ukresearchgate.netdovepress.com

Phase I Studies: Dose Escalation and Recommended Phase II Dose Determination

Phase I studies of this compound involved dose escalation to determine the maximum tolerated dose (MTD) and the recommended phase II dose (RP2D) in patients with advanced solid tumors, including those with BRAF V600 mutations. fda.govresearchgate.netnih.gov An accelerated dose titration method was employed in some studies, with initial cohorts receiving low doses that were escalated based on observed toxicities and pharmacokinetic data. nih.govclinicaltrials.gov

In one notable Phase I trial (BREAK-1), doses were escalated up to 300 mg twice daily, but an MTD was not reached. nih.govaacrjournals.org The RP2D was determined based on a comprehensive assessment of safety, pharmacokinetic, and response data. researchgate.netnih.gov This led to the selection of 150 mg twice daily as the RP2D for subsequent studies. researchgate.netnih.govaacrjournals.orgresearchgate.net

Pharmacodynamic Endpoints in Dose Selection

Pharmacodynamic endpoints played a crucial role in the selection of the RP2D for this compound. fda.govresearchgate.net These endpoints included the assessment of the inhibition of phosphorylated ERK (pERK), a downstream marker of MAPK pathway activity, in tumor tissue. guidetopharmacology.orgeuropa.eu In patients with BRAF V600 mutation-positive melanoma, administration of this compound resulted in the inhibition of tumor phosphorylated ERK relative to baseline, providing evidence of target engagement and pathway modulation. europa.eu Pharmacokinetic parameters such as maximum concentration (Cmax), time to reach maximum concentration (tmax), and area under the plasma concentration-time curve (AUC) were also characterized to understand drug exposure and its relationship with efficacy and safety. fda.govaacrjournals.org The goal was often to identify a dose that achieved systemic exposures comparable to those observed in adults in pivotal Phase III studies. aacrjournals.org

Phase III Trials (e.g., BREAK-3)

The efficacy of this compound monotherapy was further evaluated in Phase III trials, such as the BREAK-3 study. wikipedia.orgwikidata.orgascopubs.org BREAK-3 was a randomized, open-label, multicenter trial that compared this compound to dacarbazine chemotherapy in patients with previously untreated, unresectable stage III or IV BRAF V600E-mutated melanoma. ascopubs.orgnih.gov

Objective Response Rates and Duration of Response

In the BREAK-3 trial, this compound demonstrated a significantly higher objective response rate (ORR) compared to dacarbazine. The confirmed ORR was 53% for patients treated with this compound versus 19% for those receiving dacarbazine. ascopubs.orgresearchgate.net

Progression-Free Survival Outcomes

This compound significantly improved progression-free survival (PFS) compared to dacarbazine in the BREAK-3 study. ascopubs.orgnih.govresearchgate.net At the primary analysis, the median PFS was 5.1 months for the this compound arm and 2.7 months for the dacarbazine arm. ascopubs.orgresearchgate.net An updated analysis with longer follow-up confirmed the benefit, reporting a median PFS of 6.9 months for this compound and 2.7 months for dacarbazine, with a hazard ratio of 0.37. asco.org Long-term follow-up of BREAK-3 showed that the 5-year PFS rate was 12% in the this compound arm, while all patients in the dacarbazine arm had progressed or were censored by 5 years. nih.govnih.gov

Synergistic Inhibition of MAPK Pathway

This compound acts as a selective inhibitor of mutated BRAF, a key component of the Mitogen-Activated Protein Kinase (MAPK) pathway. Constitutive activation of this pathway, often due to BRAF mutations, drives uncontrolled cellular growth and proliferation in various cancers. mdpi.com While this compound monotherapy can effectively inhibit this pathway, resistance mechanisms can lead to pathway reactivation. nih.gov

Combining this compound with a MEK inhibitor, such as trametinib, offers a synergistic approach to inhibiting the MAPK pathway. nih.govcancerbiomed.org This dual inhibition targets the pathway at two different points (BRAF and MEK), which can overcome some resistance mechanisms and enhance the anti-tumor activity compared to inhibiting BRAF alone. nih.govresearchgate.netaacrjournals.org Studies have shown that this combination can prevent MAPK pathway rebound that may occur with single-agent BRAF inhibition. nih.govcancerbiomed.org

Superior Efficacy Compared to Monotherapy

Combination therapy with this compound and trametinib has resulted in higher objective response rates (ORR) compared to this compound monotherapy. In the COMBI-d study, the ORR was 67% with the combination compared to 51% with this compound alone. rug.nl Another analysis in BRAF-naive patients showed an ORR of 67.3% with the combination. nih.gov In patients with brain metastases, the ORR in BRAF-naive individuals treated with the combination was 61.3%. nih.gov

Combination therapy has also shown a significant improvement in progression-free survival (PFS). In the COMBI-d trial, the median PFS was 11.0 months with this compound plus trametinib versus 8.8 months with this compound monotherapy. nih.gov The 3-year PFS rate was 22% with the combination compared to 12% with monotherapy. nih.govresearchgate.net A 5-year pooled analysis of the COMBI-d and COMBI-v studies reported a PFS rate of 19% with the combination. dermnetnz.org In the DESCRIBE II study, the median PFS in BRAF-naive patients treated with the combination was 7.5 months, and specifically in those with brain metastases, it was 6.2 months. nih.gov

Extended Progression-Free Survival

Clinical Application in BRAF V600-Mutant Melanoma

This compound is clinically applied in the treatment of patients with melanoma harboring a BRAF V600 mutation. nih.govfda.govcda-amc.ca The presence of this specific mutation is crucial for the effectiveness of this compound.

This compound, particularly in combination with trametinib, is a standard treatment option for patients with unresectable or metastatic melanoma with BRAF V600E or V600K mutations. fda.govnih.govresearchgate.netcinj.org This combination has demonstrated significant clinical activity in this patient population. nih.gov this compound monotherapy was initially approved for unresectable or metastatic melanoma with a BRAF V600E mutation. fda.govcda-amc.ca Subsequently, the combination with trametinib received approval for patients with BRAF V600E or V600K mutations. fda.govmdpi.com The combination is supported for long-term first-line use in this setting. researchgate.net Clinical data also suggest activity of this compound in patients with brain metastases. nih.govnih.govcda-amc.ca

Adjuvant Treatment for High-Risk Melanoma

For patients with high-risk resected cutaneous melanoma harboring BRAF V600 mutations, adjuvant treatment with this compound in combination with trametinib has shown significant clinical benefit. The Phase 3 COMBI-AD trial (NCT01682083) evaluated this combination versus placebo in patients with resected Stage III BRAF-mutated melanoma. targetedonc.comlarvol.comdovepress.com

Comparative efficacy analyses suggest that this compound plus trametinib has improved efficacy over historical treatment options such as ipilimumab, interferons, and chemotherapy, and comparable efficacy to other targeted and immune checkpoint inhibitors in the adjuvant setting for high-risk melanoma. nih.govbecarispublishing.com

Activity in Brain Metastases

Melanoma brain metastases (MBM) are a significant clinical challenge, often associated with a poor prognosis. aacrjournals.orgaacrjournals.org this compound, particularly in combination with trametinib, has demonstrated activity in patients with BRAF V600-mutant melanoma who have brain metastases.

The Phase 2 COMBI-MB trial (NCT02039947) specifically evaluated the combination of this compound and trametinib in patients with BRAF V600-mutant melanoma brain metastases. nih.govaacrjournals.org In Cohort A of this trial, which included patients with BRAF V600E mutation, asymptomatic MBM, and no prior local brain therapy, the investigator-assessed intracranial response rate (IRR) was 58%. nih.govaacrjournals.org The intracranial disease control rate in this cohort was 78%. aacrjournals.org Responses were also observed in other cohorts of the COMBI-MB study, including patients with prior local brain therapy or those with BRAF V600D/K/R mutations or symptomatic MBM. nih.gov

Tissue-Agnostic Application in Other BRAF V600E-Positive Solid Tumors

The presence of BRAF V600E mutations is not limited to melanoma and is found in a variety of other solid tumors. ascopubs.orgfda.gov Based on evidence of consistent responses across different tumor types harboring this mutation, the combination of this compound and trametinib has received accelerated approval as a tissue-agnostic treatment for adult and pediatric patients aged 6 years and older with unresectable or metastatic solid tumors with a BRAF V600E mutation who have progressed following prior treatment and have no satisfactory alternative treatment options. fda.govajmc.comresearchgate.net This approval was supported by data from multi-cohort trials, including the Phase 2 Rare Oncology Agnostic Research (ROAR) trial (BRF117019) and the NCI-MATCH trial (NCT02465060). fda.govajmc.comresearchgate.net

The ROAR trial was a basket trial that explored the use of the this compound/trametinib combination in multiple tumor types harboring the BRAF V600E mutation. ascopubs.orgfda.govresearchgate.net These included anaplastic thyroid carcinoma, biliary tract cancer, low-grade glioma, high-grade glioma, and others. ascopubs.orgfda.govresearchgate.netbrainlife.org

Non-Small Cell Lung Cancer (NSCLC)

BRAF V600E mutations occur in a subset of patients with advanced non-small cell lung cancer (NSCLC). ascopubs.orgasco.orgnih.govnih.gov The combination of this compound and trametinib has demonstrated significant efficacy in this patient population. ascopubs.orgasco.orgnih.govnih.govamegroups.org

In the IFCT-2004 BLaDE study, a real-world multicenter cohort of patients with advanced BRAF V600E-mutated NSCLC, the this compound-trametinib combination showed promising results. ascopubs.orgasco.orgnih.gov In patients receiving the combination as second-line or subsequent treatment, the 12-month OS rate was 67.4%, with a median progression-free survival (mPFS) of 10.4 months. ascopubs.orgasco.orgnih.gov For patients receiving the combination as first-line treatment, the 12-month OS rate was also 67.4%, with a mPFS of 18.2 months. ascopubs.orgasco.orgnih.govnih.gov Objective response rates (ORR) were 73.8% in the second-line or subsequent setting and 82.9% in the first-line setting. ascopubs.orgasco.org These findings are consistent with registration studies and support the use of this combination in both first-line and later-line settings for BRAF V600E-mutated metastatic NSCLC. ascopubs.orgnih.gov

Anaplastic Thyroid Carcinoma

Anaplastic thyroid carcinoma (ATC) is a rare and aggressive malignancy, with a poor prognosis. nhs.walesnih.govascopubs.org BRAF V600E mutations are estimated to be present in 20%-50% of patients with ATC. ascopubs.org The combination of this compound and trametinib has shown substantial clinical benefit in patients with BRAF V600E-mutant ATC. nhs.walesnih.govascopubs.org

Evidence from the ROAR trial demonstrated the efficacy of this compound plus trametinib in ATC. ascopubs.orgnhs.walesnih.govascopubs.org An updated analysis of the ATC cohort in the ROAR trial, including 36 patients, showed an investigator-assessed ORR of 56%, with three complete responses and 17 partial responses. nhs.walesnih.gov The 12-month duration of response rate was 50%. nih.gov The median OS was 14.5 months, with a 12-month OS rate of 51.7%, which is notable given the historically poor prognosis of ATC. ascopubs.orgnhs.walesnih.gov These results confirm the definitive benefit of the combination in BRAF V600E-mutant ATC. ascopubs.orgnih.gov

Biliary Tract Cancer

BRAF V600E mutations are found in approximately 5%-7% of patients with biliary tract cancer (BTC). ascopubs.orgascopost.comascopubs.orgmdpi.com The this compound and trametinib combination has shown promising activity in this patient population. ascopubs.orgascopost.comascopubs.orgonclive.com

In the ROAR trial, the cohort of patients with BRAF V600E-mutated BTC demonstrated encouraging results. ascopubs.orgascopubs.orgonclive.com An investigator-assessed ORR of 41% was observed in evaluable patients. ascopubs.org An updated analysis reported an ORR of 47% (investigator-assessed) or 51%, with 35% of patients having stable disease, resulting in a clinical benefit rate of 81%. ascopubs.orgonclive.com The median duration of response was 9 months. ascopubs.org The median PFS was 7.2 months, and the median OS was 11.3 months in an earlier analysis. ascopubs.org A later report indicated a median PFS of 9.1 months and a median OS of 13.5 months. ascopost.com These findings suggest that the this compound plus trametinib combination is a potential treatment option for patients with BRAF V600E-mutated BTC. ascopost.comascopubs.org

Gliomas (Low-Grade and High-Grade)

BRAF V600 mutations are present in a subset of gliomas, including both low-grade glioma (LGG) and high-grade glioma (HGG). oncnursingnews.comfda.govasco.orgmdpi.comnih.govesmo.org The combination of this compound and trametinib has shown clinically meaningful activity in patients with BRAF V600E-mutated recurrent or refractory gliomas. nih.govesmo.orgresearchgate.net

In the ROAR trial, the combination was evaluated in patients with BRAF V600E-mutated LGG and HGG. fda.govbrainlife.orgmdpi.comnih.gov In the LGG cohort, the investigator-assessed ORR was 69%. nih.govresearchgate.net This included one complete response, six partial responses, and two minor responses among 13 evaluable patients. nih.govresearchgate.net The median duration of response by independent radiology review was 27.5 months. oncnursingnews.com

In pediatric patients with relapsed/refractory BRAF V600-mutated high-grade glioma, treatment with this compound plus trametinib was associated with an independently assessed ORR of 56% and a median duration of response of 22.2 months in a Phase 2 study. esmo.org For pediatric patients with BRAF V600-mutant LGG, this compound monotherapy demonstrated an ORR of 44% and a 1-year progression-free survival rate of 85% in a Phase 1/2a study. aacrjournals.org

Here are some of the detailed research findings in data tables:

Table 1: Efficacy of this compound + Trametinib in BRAF V600E-Mutated Solid Tumors (Selected Data)

Table 2: BRAF V600E Mutation Frequency in Selected Tumor Types

Langerhans Cell Histiocytosis (LCH)

Langerhans cell histiocytosis is a rare neoplastic disorder, predominantly affecting children, where BRAF mutations are identified in over 50% of patients. ashpublications.orgnih.gove-crt.org Clinical studies have investigated the use of this compound, alone or with trametinib, in pediatric patients with BRAF V600-mutant, recurrent/refractory LCH. ashpublications.orgnih.gov

Two open-label phase 1/2 studies evaluated this compound monotherapy (CDRB436A2102; NCT01677741) and this compound plus trametinib (CTMT212X2101; NCT02124772) in this population. ashpublications.orgnih.gov

Table 1: Objective Response Rates in Pediatric BRAF V600-Mutant LCH

Hairy Cell Leukemia

Hairy cell leukemia is another rare cancer where BRAF V600E mutations are frequently observed, in 79-100% of cases. esmo.org The combination of this compound and trametinib has been investigated in patients with BRAF V600E-mutated rare cancers, including hairy cell leukemia, as part of the Phase II ROAR basket study (NCT02034110). esmo.orgmycancergenome.org This study aimed to determine the ORR of the combination in various rare cancers with the BRAF V600E mutation. mycancergenome.org

Colorectal Cancer (in combination with EGFR inhibitors)

In contrast to melanoma, BRAF inhibitor monotherapy has shown limited efficacy in BRAF V600E-mutant colorectal cancer (CRC), with response rates around 5%. nih.govascopost.com Preclinical studies suggest that this is due to adaptive feedback reactivation of the MAPK pathway, often mediated by EGFR. nih.govamegroups.org Therefore, research has focused on combining BRAF inhibitors with EGFR inhibitors to overcome this resistance. nih.govamegroups.orgmdpi.com

Clinical trials have evaluated the combination of this compound with anti-EGFR therapies, sometimes including a MEK inhibitor. An initial trial combining this compound and the anti-EGFR monoclonal antibody panitumumab showed responses in 2 out of 10 BRAF V600E-mutant mCRC patients (20%) with a median PFS of 3.4 months. amegroups.orggencat.cat A three-drug combination of this compound, trametinib, and panitumumab was tested, showing response rates of 21% and a median PFS of 4.2 months in one trial. nih.govmdpi.com Another study of the triple combination in 15 patients showed an initial response rate of 40%, with an additional 40% achieving stable disease. amegroups.org

Table 2: Select Clinical Trial Findings in BRAF V600E-Mutant Colorectal Cancer

While dual and triple blockade strategies have shown promising activity compared to BRAF inhibitor monotherapy in BRAF V600E CRC, overcoming MAPK reactivation remains a challenge. nih.gov

Other Rare Cancers

This compound, particularly in combination with trametinib, has demonstrated activity in a variety of other rare cancers harboring the BRAF V600E mutation. ascopubs.orgesmo.org The ROAR basket study (NCT02034110) included cohorts for several rare tumor types with the BRAF V600E mutation, such as anaplastic thyroid cancer, biliary tract cancer, gastrointestinal stromal tumor, non-seminomatous germ cell tumor, World Health Organization (WHO) Grade 1 or 2 glioma, WHO Grade 3 or 4 (high-grade) glioma, multiple myeloma, and adenocarcinoma of the small intestine. esmo.orgmycancergenome.org

The combination of this compound and trametinib received accelerated approval from the FDA in 2022 for the treatment of patients with BRAF V600E-mutated unresectable or metastatic tumors and progressive disease after prior therapy, based on data showing durable and clinically significant responses across 21 histologies in the ROAR study. esmo.orgvhio.netascopubs.org This marked a significant step towards tumor-agnostic therapy for BRAF-mutated rare cancers. esmo.orgvhio.net The NCI-MATCH trial also reported an ORR of 38% with this compound plus trametinib in patients with BRAF mutation-positive solid tumors and lymphomas, corroborating the findings of the ROAR study. ascopubs.org

Evaluation of Intracranial Activity in Specific Populations

This compound has shown activity in melanoma brain metastases. nih.govmdanderson.orgresearchgate.netdermnetnz.org A phase I study reported that this compound shrank tumors that had spread to the brain in 9 out of 10 patients with BRAF V600-mutant melanoma with previously untreated brain metastases. mdanderson.orgdermnetnz.org The phase II BREAK-MB study (NCT01729268) further assessed this compound in BRAF V600E/K mutation-positive melanoma patients with brain metastases, showing intracranial response rates ranging between 31% and 39%. researchgate.net The combination of this compound plus trametinib achieved an intracranial response rate of 58% in melanoma that had metastasized to the brain in the COMBI-MB trial. targetedonc.comaacrjournals.org Future research aims to further evaluate the intracranial activity of this compound, potentially in combination with other agents, in specific patient populations and tumor types with brain involvement.

Combination with Immunotherapies

Combining targeted therapies like BRAF and MEK inhibitors with immunotherapies is an active area of research, aiming to achieve more durable responses. tu-dresden.debmj.comnih.gov Preclinical data suggest that BRAF and MEK inhibitors can create an immune-stimulating tumor microenvironment and increase immune cell infiltration. tu-dresden.de

Research is also ongoing to evaluate the combination of this compound, trametinib, and immunotherapy in BRAF V600E-mutated colorectal cancer, where immunotherapy alone has shown limited efficacy in microsatellite stable tumors. ascopost.com Early findings suggest that this triplet combination may result in long-lasting responses in this setting. ascopost.com

Exploration of Alternative BRAF Mutations Beyond V600E

While BRAF V600E mutations are the most common BRAF alteration in various cancers, particularly melanoma and non-small cell lung cancer (NSCLC), other non-V600E BRAF mutations exist and can also drive oncogenic signaling mdpi.comfrontiersin.org. Clinical research has extended to investigate the efficacy of BRAF inhibitors like this compound, often in combination with MEK inhibitors such as trametinib, in these less frequent BRAF alterations.

Studies in NSCLC, for instance, have indicated that while registrational trials for this compound plus trametinib primarily enrolled patients with BRAF V600E mutations, data on the treatment of patients with non-V600E BRAF mutations are emerging from case reports and retrospective analyses mdpi.comdovepress.com. Some non-V600E mutations, such as G469A and L597R, which are associated with high kinase activity, have shown associations with response to BRAF and MEK inhibitors mdpi.com. Preclinical studies in NSCLC cell lines have also supported the efficacy of BRAF and MEK inhibition in certain non-V600E mutations like G469A and G466V mdpi.com.

A case report highlighted the efficacy of the combination of this compound and trametinib in a pediatric ganglioglioma harboring a BRAF p.T599dup mutation, demonstrating stable disease and improved neurological symptoms researchgate.net. This suggests potential activity of the combination in specific non-V600E alterations beyond the more commonly targeted V600E/K.

Retrospective analyses in NSCLC patients with non-V600E BRAF mutations have reported varying objective response rates (ORR) and progression-free survival (PFS) outcomes with targeted therapy, including this compound combinations mdpi.comamegroups.org. One retrospective analysis of 30 patients with non-V600E mutated NSCLC who received targeted therapy reported a median PFS of 3.6 months mdpi.com. Another retrospective chart review of 39 patients with BRAF-mutant NSCLC (21 V600E, 18 non-V600E) reported ORRs of 25% and 33% and median PFS of 3.7 months and 4.1 months, respectively, in those who received immunotherapies mdpi.com. Some studies suggest that immunotherapy might show activity in non-V600E BRAF mutations in NSCLC mdpi.comfrontiersin.org.

The clinical activity of this compound plus trametinib has been observed in various tumor types harboring BRAF V600E mutations, leading to tissue-agnostic approvals ascopubs.org. While the focus has been on V600E, the exploration of its effectiveness in other BRAF mutations continues to be an area of research to potentially expand the clinical utility of this compound.

Novel Treatment Sequencing Strategies

The optimal sequencing of different therapeutic modalities, particularly targeted therapy with BRAF/MEK inhibitors and immunotherapy, has been a critical area of investigation in the management of BRAF-mutant cancers, especially melanoma targetedonc.comtargetedonc.comcancerworld.net.

The phase 3 DREAMseq trial (ECOG-ACRIN EA6134; NCT02224781) prospectively compared two treatment sequences in patients with treatment-naive BRAF V600-mutant metastatic melanoma: initial treatment with combination nivolumab and ipilimumab followed by this compound and trametinib upon progression (Arm A), versus initial treatment with this compound and trametinib followed by nivolumab and ipilimumab upon progression (Arm B) targetedonc.comcancerworld.net.

These findings suggest that for most patients with metastatic BRAF V600-mutant melanoma, initiating treatment with combination immunotherapy followed by BRAF/MEK inhibitor therapy if needed, is the preferred sequence targetedonc.comcancerworld.net.

Beyond this specific sequence, research continues to explore other novel strategies, including the potential synergy of combining targeted and immunotherapeutic agents concurrently targetedonc.com. Early reports from studies evaluating triple combinations, such as a PD-L1 agent with this compound and trametinib, have shown promising clinical efficacy targetedonc.com.

Intermittent Versus Continuous Dosing Regimens

The optimal dosing schedule for BRAF and MEK inhibitor combinations like this compound and trametinib has been investigated, with a particular interest in whether intermittent dosing could potentially delay the development of acquired resistance observed with continuous treatment nih.govresearchgate.netascopubs.org. Preclinical models had suggested that intermittent BRAF inhibitor therapy might achieve this by preventing resistant cell populations from becoming dominant nih.govascopubs.org.

The randomized phase 2 SWOG S1320 trial (NCT02196181) directly compared continuous dosing of this compound and trametinib with an intermittent schedule (5 weeks on, 3 weeks off) in patients with metastatic and unresectable BRAF V600E/K mutant melanoma nih.govresearchgate.netascopubs.orgascopost.comonclive.com. Patients initially received continuous therapy for an 8-week lead-in period before being randomized if their disease had not progressed nih.govascopubs.org.

Contrary to the initial hypothesis based on preclinical data, the SWOG S1320 trial found that continuous dosing resulted in superior progression-free survival compared to the intermittent dosing schedule tested nih.govresearchgate.netascopost.comonclive.com. The median progression-free survival was 9.0 months in the continuous arm versus 5.5 months in the intermittent arm nih.govascopost.comonclive.com.

Another phase 2 study, the INTERIM trial, also evaluated intermittent versus continuous dosing of this compound plus trametinib in BRAF V600 mutant advanced melanoma using a different intermittent schedule (this compound days 1-21, trametinib days 1-14 every 28 days) nih.gov. This trial similarly concluded that intermittent dosing was inferior in all efficacy measures compared to continuous dosing, with a median PFS of 8.5 months for intermittent versus 10.7 months for continuous dosing nih.gov.

These clinical trial results from SWOG S1320 and INTERIM did not support the hypothesis that the tested intermittent dosing schedules improve efficacy compared to continuous administration of this compound and trametinib in BRAF V600-mutant melanoma nih.govnih.gov.