Efficacy Of Dabrafenib Research Articles

The safety and efficacy of dabrafenib and trametinib in patients with glioma: A systematic review and meta-analysis.

Dabrafenib and trametinib represent targeted therapy options under investigation for treatment of gliomas harboring BRAF V600 mutations. We systematically reviewed the literature and conducted meta-analyses to assess the efficacy and safety of these agents. PubMed, Embase, and Scopus were searched from inception to September 2023 for studies examining dabrafenib and/or trametinib for gliomas. Outcomes included response rates (ORR, CR, PR), progression rates (PD), 6- and 12-month PFS, adverse events, and dosing modifications. Meta-analyses were conducted using random effect models. Nine studies met the inclusion criteria. Meta-analysis demonstrated overall response rates (ORR) of 50% (95% confidence interval (CI): 35-65%) for low-grade gliomas (LGG) and 40% (95% CI: 29-51%) for high-grade gliomas (HGG). Pooled ORR was 45% (95% CI: 36-54%) for both glioma grades. The complete response rate was 13% (95% CI: 05-27%) for HGG and 5% (95% CI: 1-10%) for both LGG and HGG. Six-month progression-free survival (PFS) rates reached 87% in LGG and 67% in HGG and a pooled 6-month PFS 78% (95% CI: 58-98%), declining at 12 months to 67% and 44%, respectively, with a pooled 12-month PFS 56% (95% CI: 34-79%). Grade 1-4 adverse events occurred in 100% of LGG and 63% of HGG patients. Dabrafenib and trametinib demonstrate promising anti-tumor efficacy in gliomas, particularly low-grade tumors, achieving durable disease stabilization in many patients. However, toxicity significantly limited tolerability. Additional research should further examine efficacy and refine safe administration protocols across glioma subtypes.

Abstract LB-122: Combinations of SHP2 inhibitor to overcome RAS activation by receptor tyrosine kinases in response to ERK inhibition

Abstract Introduction: The RTK-RAS-MAPK pathway is frequently activated in cancers due to a variety of mechanisms including mutations or amplifications in RTK, KRAS or BRAF. The effectiveness of inhibitors targeting those oncogenic drivers is often limited by the pathway feedback activation originated at the RTK level in response to ERK inhibition. The non-receptor protein tyrosine phosphatase SHP2 mediates RAS activation downstream of various receptor tyrosine kinases. Potent and selective allosteric SHP2 inhibitors such as TNO155 are in clinical development and offer an appealing one-size-fits-all approach to overcome RTK-mediated feedback activation of RAS and enhance the efficacy of inhibitors targeting RTK, BRAF or KRASG12C. We sought to study the combination efficacy and mechanism in pre-clinical models for prioritization in clinical trials. Experimental procedures: The combination efficacy and synergy of TNO155 with EGF816 (a 3rd generation EGFR inhibitor), dabrafenib+trametinib or a tool KRAS G12C inhibitor (G12Ci) were respectively assessed in a number of EGFR mutant lung cancer models, BRAFV600E colorectal cancer models and KRASG12C lung and colorectal cancer models. The effect of the combinations on ERK inhibition was also studied. Results: TNO155 has varying single agent activity in vitro in EGFR mutant lung cancer cell lines and is not affected by clinically relevant resistance mechanisms to EGFR inhibitors such as secondary mutations in EGFR (T790M and C797S) or MET amplification. In addition, the combination of TNO155 and EGF816 is synergistic across cell lines, coincident with sustained ERK inhibition. In BRAFV600E colorectal cancer cell lines with feedback activation of EGFR, MET or FGFR respectively in response to treatment with dabrafenib+trametinib, TNO155 synergistically enhanced the efficacy of dabrafenib+trametinib in all three cell lines, phenocopying respective RTK inhibitors. In KRASG12C lung cancer cell lines, quick rebound of p-ERK was observed as early as 24 hour post treatment with G12Ci and cannot be blocked by increasing concentrations of G12Ci, suggesting feedback activation of wild-type KRAS or other RAS isoforms. In contrast, TNO155 effectively blocked the p-ERK rebound and enhanced the efficacy of G12Ci. Similar observations were made in KRASG12C colorectal cancer cell lines. Conclusions: Our findings suggest that SHP2 inhibition is an effective strategy to block the feedback activation of wild type and G12C KRAS, as well as NRAS and HRAS, by a variety of RTKs, in response to ERK inhibition. Given the mutant selective properties of those inhibitors we studied, the tolerability of their combinations with TNO155 is highly expected. Our data provide pre-clinical rationale to explore those TNO155 combinations in the corresponding cancer indications in clinic. Citation Format: Huaixiang Hao, Chen Liu, Hongyun Wang, Hengyu Lu, Scott Delach, Matthew LaMarche, Jeffrey Engelman, Peter Hammerman, Giordano Caponigro, Susan Moody, Morvarid Mohseni. Combinations of SHP2 inhibitor to overcome RAS activation by receptor tyrosine kinases in response to ERK inhibition [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr LB-122.

Real-world efficacy and safety data for dabrafenib and trametinib combination therapy in Japanese patients with BRAF V600 mutation-positive advanced melanoma.

We conducted a retrospective investigation of the efficacy and safety of dabrafenib and trametinib combination therapy in Japanese patients with BRAF V600 mutation-positive advanced melanoma in real-world clinical practise. The study analyzed 50 patients who received dabrafenib and trametinib combination therapy for BRAF V600 mutation-positive advanced melanoma in our hospital (26 men and 24 women, aged 21-86years, inclusive; median age, 53years). The response rate was 72.3%, with complete response (CR) achieved in eight cases (17.0%), partial response in 26 (55.3%), stable disease in nine (19.1%) and progressive disease in four (8.5%). Median progression-free survival (PFS) was 12months, and median overall survival (OS) was 23months. Disease progression occurred in 29 of the 50 patients during the study period, and 25 patients died. Baseline lactate dehydrogenase and the number of organs with metastasis were important predictive factors for PFS and OS, and CR to combination therapy was a predictive factor for long-term remission. Adverse events occurred in 88% of cases; 16% were grade 3 or worse. The adverse events observed in 50% of more of patients were rash (56%) and pyrexia (52%). The efficacy of dabrafenib and trametinib combination therapy in Japanese patients was similar to that reported in global studies, and the same adverse events were generally reported; however, rash tended to occur more frequently in the patients in our study.

Determining Resistance Mechanisms in BRAF-mutated Multiple Myeloma

Introduction: Constant clonal evolution and outgrowth of clones that harbor resistance mutations are likely explanations for the emergence of drug-resistant disease in multiple myeloma (MM). Activating mutations in BRAF, KRAS and NRAS have been suggested as potential therapeutic targets. In this study, we investigate resistance to BRAF inhibition in the context of BRAF-mutated MM which accounts for about 5-12% of all patients with relapsed/ refractory MM. Methods: Resistance to dabrafenib was modeled in vitro in the BRAF-mutated MM cell lines (MMCL) U266 (K601Nmut) and DP6 (BRAFV600Emut). Low-pass whole genome sequencing (LPWGS), RNA sequencing, ChIP sequencing and immunoblotting were performed for genomic, transcriptomic, epigenomic and molecular characterization. Functional validation was performed by genome editing using CRISPR/Cas9 technology. Results: Modeling of dabrafenib resistance in vitro revealed an initial decline of cell numbers, followed by a plateau phase and a gradual outgrowth of resistant cells after ~80 days of treatment. As expected, exposure of BRAFmut MMCL to dabrafenib led to initial downregulation of pERK and pMEK. At later timepoints, upregulation of pERK and pMEK was observed, suggesting that re-activation of the ERK/MEK pathway ultimately overcomes BRAF inhibition. This outgrowth was associated with highly distinct copy number profiles in each resistant clone, implying clonal selection with outgrowth of genetically resistant clones as one mechanism of drug resistance in MM. Additionally, we found that BRAF inhibition of BRAFmut MMCL promotes changes of the transcriptional circuitry that appears independent of clonal outgrowth of genetically resistant clones. These transcriptional changes were highly homogenous, occurred as early as 7-14 days after starting treatment and were associated with de-differentiation of MMCL into a more immature B lymphocytic phenotype. This phenotype was associated with greater mRNA expression of CD19 and CD81, as well as upregulation of the B-lymphocyte activation antigen B7-2 (CD86) and PI3K pathway genes. We next investigated if targeting the PI3K pathway and B7.2 can be exploited for effective killing of dabrafenib-resistant BRAFmut MM cells. Studies for the PI3Kδ inhibitor idelalisib in dabrafenib-persistent MMCL revealed higher sensitivity as compared to dabrafenib-naïve controls. Genome editing suggests a survival advantage for CD86WT as compared to CD86KO MMCL. Conclusions: Our data suggest that resistance to BRAF inhibition in vitro is mediated by two distinct mechanisms: 1) clonal outgrowth of genetically distinct resistant clones, and 2) transcriptional rewiring that leads to activation of alternative signaling pathways. The latter is characterized by changes in cellular differentiation and upregulation of PI3K and CD28/CD86 signaling. These concepts may provide a framework for revealing therapeutic vulnerabilities and to overcome drug resistance mediated by genetic heterogeneity in MM. Disclosures Munshi: Oncopep: Consultancy; Takeda: Consultancy; Janssen: Consultancy; Celgene: Consultancy; Oncopep: Consultancy; Abbvie: Consultancy; Adaptive: Consultancy; Amgen: Consultancy. Anderson:Sanofi-Aventis: Other: Advisory Board; Bristol-Myers Squibb: Other: Scientific Founder; Oncopep: Other: Scientific Founder; Amgen: Consultancy, Speakers Bureau; Janssen: Consultancy, Speakers Bureau; Takeda: Consultancy, Speakers Bureau; Celgene: Consultancy, Speakers Bureau. Yee:Karyopharm: Consultancy; Bristol-Myers Squibb: Consultancy, Research Funding; Amgen: Consultancy, Honoraria; Celgene: Consultancy, Honoraria, Research Funding; Takeda: Consultancy; Adaptive: Consultancy. Raje:Amgen Inc.: Consultancy; Bristol-Myers Squibb: Consultancy; Celgene Corporation: Consultancy; Takeda: Consultancy; Janssen: Consultancy; Merck: Consultancy. Lohr:Celgene: Research Funding; T2 Biosystems: Honoraria. OffLabel Disclosure: Dabrafenib is a potent inhibitor of BRAF mutated at codon 600 (BRAFV600). Here we explored the efficacy of dabrafenib a preclinical model of multiple myeloma cell lines with BRAFV600E and BRAFK601N mutations.

The safety and efficacy of dabrafenib and trametinib for the treatment of melanoma

ABSTRACTIntroduction: The introduction of BRAF and MEK inhibitors into clinical practice improved the prognosis of metastatic melanoma patients. The combination of BRAF inhibitor dabrafenib with MEK inhibitor trametinib has shown its superiority to single agent therapy and is characterized by a tolerable spectrum of adverse events which shows a decrease in incidence over time on treatment.Areas covered: The current scientific literature on safety and adverse events (AEs) related to BRAF and MEK-inhibition has been investigated with special focus on the large phase 3 studies (COMBI-v, COMBI-d and CoBRIM) as well as recent updates presented at oncology and melanoma meetings. Additionally, published case series/case reports were screened for information on AEs.Expert opinion: Even though almost every patient (98%) under combination therapy with dabrafenib and trametinib experiences at least one adverse event, these are generally mild to moderate, reversible and can be managed with dose reductions or interruptions. However, due to an increased life expectancy, there is a substantial need to prevent and treat also mild adverse events, as they play a central role for the quality of life of patients. Ongoing clinical trials will have to demonstrate the efficacy as well as safety of triple combination with anti-PD-1/anti-PD-L1 antibodies.

Efficacy of dabrafenib (D) and trametinib (T) in patients (pts) with BRAF V600E–mutated anaplastic thyroid cancer (ATC).

6023 Background: ATC is a rare, aggressive malignancy with a dismal prognosis. Median overall survival (OS) is < 6 mo. Combined BRAF and MEK inhibition is efficacious in BRAF V600–mutated melanoma and lung cancer. One-fourth of ATCs harbor activating BRAF V600E mutations; thus, D (BRAF inhibitor) + T (MEK inhibitor) was evaluated as a treatment for pts with BRAF V600E–mutated ATC. Methods: In this phase 2, open-label trial (NCT02034110), pts with BRAF V600E mutations in 9 rare tumor types, including ATC, received continuous D (150 mg BID) + T (2 mg QD) until unacceptable toxicity, disease progression, or death. Eligible pts had advanced or metastatic cancer with no standard-of-care treatment options. The primary endpoint was investigator-assessed overall response rate (ORR). Secondary endpoints included duration of response (DOR), progression-free survival (PFS), OS, and safety. We report data from the ATC cohort. Results: 16 pts with BRAF V600E–mutated ATC had evaluable data with a median follow-up time of 47 wk (range 4-120 wk). BRAF V600E mutations were centrally confirmed in 15/16 pts. Median age was 72 y; all 16 pts had undergone prior tumor radiation and/or surgery and 6/16 pts (38%) had received ≥1 prior line of systemic therapy. Investigator-assessed confirmed ORR was 69% (11/16; 95% CI, 41%-89%), with 7/11 responses ongoing at the time of data cut. The Bayesian estimate of ORR was 69% (95% credible interval, 47%-87%) with a 100% probability that this ORR exceeded the 15% historical RR. Median DOR, PFS, and OS were not estimable due to insufficient progression and death events. Kaplan-Meier estimates of DOR, PFS, and OS at 12 mo were 90%, 79%, and 80%, respectively. The safety population comprised 100 pts enrolled in 7/9 histologies. Among all pts, 92% had an AE. Common AEs of any grade for all histologies were fatigue (38%), pyrexia (37%), and nausea (35%). In the ATC cohort, the most common grade 3/4 events were hyponatremia (19%), pneumonia (13%), and anemia (13%). Conclusions: D+T combination therapy significantly improved outcomes in ATC with a favorable safety profile. This regimen represents a clinically meaningful therapeutic advance for pts with advanced/metastatic BRAF V600–mutated ATC. Clinical trial information: NCT02034110.

346PD Evaluation of safety, tolerability, pharmacokinetics (PK) and efficacy of dabrafenib and trametinib combination (Dab + Tra) therapy in Japanese patients (pts) with BRAF V600 mutation-positive advanced cutaneous melanoma: a phase (Ph) I/II study

Aim/Background: Combination of dabrafenib (Dab, 150 mg twice daily [BID]), a BRAF inhibitor, and trametinib (Tra, 2 mg once daily [QD]), a MEK inhibitor, is clinically active in BRAF V600 mutation-positive metastatic melanoma, and approved in the US and elsewhere. The tolerability, safety, PK and efficacy of the combination in Asians have not been evaluated. We investigated this combination in Japanese pts. Methods: In Ph I, pts with BRAF V600E/K mutation-positive advanced solid tumors, refractory to standard therapies, received Dab 150 mg BID + Tra 2 mg QD; dose-limiting toxicity, safety and PK were assessed. In Ph II, pts with BRAF V600E/K mutation-positive unresectable (stage IIIC) or metastatic (stage IV) cutaneous melanoma were enrolled and the confirmed overall response rate (ORR) was evaluated (NCT01928940). Results: Japanese pts with BRAF V600E mutation-positive advanced cutaneous melanoma (n = 12) received Dab + Tra (6 in Ph I and 6 in Ph II), and comprised 7 men and 5 women. Mean age was 55.6 years (range 21–77). No DLT was seen in Ph I. AEs (≥ 50%) reported in Ph I were pyrexia, nasopharyngitis, rash maculo-papular, erythema, aspartate aminotransferase (AST) increased, decreased appetite, headache, alopecia, dermatitis acneiform, and blood alkaline phosphatase increased. AEs (≥ 50%) reported in Ph II were pyrexia, oedema peripheral, AST increased, and stomatitis. No squamous cell carcinoma was seen. PK results in repeat dosing in Ph I showed absorption of both drugs was rapid with a median plasma Tmax of ≈2 h for Dab and 1 h for Tra. Steady-state was achieved within ≈21 days after the first dose of Tra. Best confirmed responses per investigator in Ph II (n = 6) were 2 (33%) complete responses (CR), 3 (50%) partial responses (PR) and 1 (17%) stable disease. The confirmed ORR (CR + PR) was 83% (95% CI 35.9–99.6). Conclusions: Dab + Tra was well tolerated with a manageable safety profile in Japanese pts, and clinically meaningful antitumor activity was seen. Japanese clinical and PK outcomes were comparable to those of Caucasian pts. Dab + Tra should be further investigated in Japanese pts. Clinical trial identification: NCT01928940 Disclosure: Y. Fujiwara: research funding: AstraZeneca, Chugai, Eisai, Eli Lilly, GlaxoSmithKline. A. Suzuki: other substantive relationships: GlaxoSmithKline; employee until 30 April 2015; currently a Novartis Pharma employee as of 1 May 2015. A. Mukaiyama: stock ownership: GlaxoSmithKline. Y. Kiyohara: research funding: Ono Pharmaceutical, Chugai Pharmaceutical Co, BMS, MSD, Merck Serono, GSK; other substantive relationships: Ono Pharamceutical, received payment in role of safety review; Chugai Pharmaceutical Co, received renumeration as a speaker. All other authors have declared no conflicts of interest.

Evaluation of Safety, Tolerability, Pharmacokinetics and Efficacy of Dabrafenib, a Braf Inhibitor, in Japanese Patients with Braf V600 Mutation-Positive Advanced Solid Tumors: a Phase I Study

ABSTRACT Aim: Dabrafenib, a potent and selective BRAF inhibitor, has demonstrated clinical significance for BRAF V600 mutation-positive metastatic melanoma and has been approved in the US and EU. However, there is less clinical experience of treatment with dabrafenib in the Japanese population. Therefore, this study has been designed and conducted to evaluate safety, tolerability, pharmacokinetics (PK) and efficacy of dabrafenib in Japanese patients with BRAF V600 mutation-positive advanced solid tumors as the first clinical trial. Methods: Patients with BRAF V600 mutation-positive advanced solid tumors refractory to standard therapies were enrolled. Dose escalation was performed according to a standard 3 + 3 design. Dabrafenib was given twice a day (BID), which started 7 days after a single dose administration for a single-dose PK analysis. Antitumor activity was evaluated based on RECIST version 1.1. This study was registered at www.clinicaltrials.gov as NCT01582997. Results: Twelve patients (11 melanoma and 1 papillary thyroid cancer) with BRAF V600E mutation received dabrafenib at doses of 75 mg (n = 3), 100 mg (n = 3), or 150 mg (n = 6). The median duration of treatment was approximately 39 weeks. No dose-limiting toxicities were observed in these three dose cohorts. The most common adverse events (AEs) included alopecia, leucopenia, pyrexia and arthralgia. Most AEs were reported as grade 1 or 2. Squamous-cell carcinoma or keratoacanthoma, which is a well-documented BRAF inhibitor class toxicity, was not observed in this study. Preliminary PK results showed no obvious ethnic difference. Partial responses were confirmed in 7 patients (58.3%), 6 melanoma patients and 1 papillary thyroid cancer patient. The data also suggested dabrafenib had an antitumor activity in Japanese patients with BRAF V600 mutation-positive melanoma as well as papillary thyroid cancer. Conclusions: Compared with the data published for the caucasian population, dabrafenib exhibited comparable tolerability, safety and PK profiles in Japanese patients at the dose of 150 mg BID. This dose also gave a suggestive outcome for the potential efficacy to the Japanese population. Disclosure: A. Suzuki: A. Suzuki is an employee of GlaxoSmithKline K.K; A. Mukaiyama: A. Mukaiyama is an employee of GlaxoSmithKline K.K. All other authors have declared no conflicts of interest.