70 results on '"Eduard Gasal"'
Search Results
2. KEYNOTE-022 part 3: a randomized, double-blind, phase 2 study of pembrolizumab, dabrafenib, and trametinib in BRAF-mutant melanoma
- Author
-
Antoni Ribas, Inge Marie Svane, Paolo Antonio Ascierto, Victoria Atkinson, Razi Ghori, Anna Maria Di Giacomo, Georgina V Long, Henrik Schmidt, Jacob Schachter, Eduard Gasal, Paola Queirolo, Michal Lotem, Michele Del Vecchio, Pier Francesco Ferrucci, Rosalie Stephens, Mahmoud Abu-Amna, Scott J Diede, and Elizabeth S Croydon
- Subjects
Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Abstract
Background In the KEYNOTE-022 study, pembrolizumab with dabrafenib and trametinib (triplet) improved progression-free survival (PFS) versus placebo with dabrafenib and trametinib (doublet) without reaching statistical significance. Mature results on PFS, duration of response (DOR), and overall survival (OS) are reported.Methods The double-blind, phase 2 part of KEYNOTE-022 enrolled patients with previously untreated BRAFV600E/K-mutated advanced melanoma from 22 sites in seven countries. Patients were randomly assigned 1:1 to intravenous pembrolizumab (200 mg every 3 weeks) or placebo plus dabrafenib (150 mg orally two times per day) and trametinib (2 mg orally one time a day). Primary endpoint was PFS. Secondary endpoints were objective response rate, DOR, and OS. Efficacy was assessed in the intention-to-treat population, and safety was assessed in all patients who received at least one dose of study drug. This analysis was not specified in the protocol.Results Between November 30, 2015 and April 24, 2017, 120 patients were randomly assigned to triplet (n=60) or doublet (n=60) therapy. With 36.6 months of follow-up, median PFS was 16.9 months (95% CI 11.3 to 27.9) with triplet and 10.7 months (95% CI 7.2 to 16.8) with doublet (HR 0.53; 95% CI 0.34 to 0.83). With triplet and doublet, respectively, PFS at 24 months was 41.0% (95% CI 27.4% to 54.2%) and 16.3% (95% CI 8.1% to 27.1%); median DOR was 25.1 months (95% CI 14.1 to not reached) and 12.1 months (95% CI 6.0 to 15.7), respectively. Median OS was not reached with triplet and was 26.3 months with doublet (HR 0.64; 95% CI 0.38 to 1.06). With triplet and doublet, respectively, OS at 24 months was 63.0% (95% CI 49.4% to 73.9%) and 51.7% (95% CI 38.4% to 63.4%). Grade 3–5 treatment-related adverse events (TRAEs) occurred in 35 patients (58%, including one death) receiving triplet and 15 patients (25%) receiving doublet.Conclusion In BRAFV600E/K-mutant advanced melanoma, pembrolizumab plus dabrafenib and trametinib substantially improved PFS, DOR, and OS with a higher incidence of TRAEs. Interpretation of these results is limited by the post hoc nature of the analysis.
- Published
- 2020
- Full Text
- View/download PDF
3. Reimagining patient-centric cancer clinical trials: a multi-stakeholder international coalition
- Author
-
Bob T. Li, Bobby Daly, Mary Gospodarowicz, Monica M. Bertagnolli, Otis W. Brawley, Bruce A. Chabner, Lola Fashoyin-Aje, R. Angelo de Claro, Elizabeth Franklin, Jennifer Mills, Jeff Legos, Karen Kaucic, Mark Li, Lydia The, Tina Hou, Ting-Hui Wu, Bjorn Albrecht, Yi Shao, Justin Finnegan, Jing Qian, Javad Shahidi, Eduard Gasal, Craig Tendler, Geoffrey Kim, James Yan, Phuong Khanh Morrow, Charles S. Fuchs, Lianshan Zhang, Robert LaCaze, Stefan Oelrich, Martin J. Murphy, Richard Pazdur, Kevin Rudd, and Yi-Long Wu
- Subjects
Clinical Trials as Topic ,Neoplasms ,Patient-Centered Care ,Humans ,General Medicine ,General Biochemistry, Genetics and Molecular Biology - Published
- 2022
4. Supplementary Figures from Role of Tumor-Infiltrating B Cells in Clinical Outcome of Patients with Melanoma Treated With Dabrafenib Plus Trametinib
- Author
-
Alexander Roesch, Dirk Schadendorf, Eduard Gasal, Elisabeth Livingstone, Lisa Zimmer, Kurt W. Schmid, Antje Sucker, Jacob Schachter, Boguslawa Karaszewska, Keith T. Flaherty, Antoni Ribas, Paul D. Nathan, Georgina V. Long, Caroline Robert, Ken Schultz, Naveen Dakappagari, Ju Kim, Deborah Castelletti, Renata Varaljai, Tobias Schimming, James Garrett, Daniel Gusenleitner, Alexander Savchenko, Robert F.H. Walter, and Jan C. Brase
- Abstract
Supplementary Figures from Role of Tumor-Infiltrating B Cells in Clinical Outcome of Patients with Melanoma Treated With Dabrafenib Plus Trametinib
- Published
- 2023
5. Data from BRAF-Mutant Transcriptional Subtypes Predict Outcome of Combined BRAF, MEK, and EGFR Blockade with Dabrafenib, Trametinib, and Panitumumab in Patients with Colorectal Cancer
- Author
-
Ryan B. Corcoran, Eduard Gasal, Fatima Rangwala, Jan C. Brase, John M. Millholland, Eric Van Cutsem, Filip De Vos, Peter J. O'Dwyer, Rona Yaeger, Josep Tabernero, Michael S. Gordon, Salvatore Siena, Autumn J. McRee, Antoine Hollebecque, Johanna C. Bendell, Takayuki Yoshino, Jan H.M. Schellens, Chloe E. Atreya, Thierry André, Catarina D. Campbell, Yiqun Yang, and Gary Middleton
- Abstract
Purpose:The influence of the transcriptional and immunologic context of mutations on therapeutic outcomes with targeted therapy in cancer has not been well defined. BRAF V600E–mutant (BM) colorectal cancer comprises two main transcriptional subtypes, BM1 and BM2. We sought to determine the impact of BM subtype, as well as distinct biological features of those subtypes, on response to BRAF/MEK/EGFR inhibition in patients with colorectal cancer.Patients and Methods:Paired fresh tumor biopsies were acquired at baseline and on day 15 of treatment from all consenting patients with BM colorectal cancer enrolled in a phase II clinical trial of dabrafenib, trametinib, and panitumumab. For each sample, BM subtype, cell cycle, and immune gene signature expression were determined using RNA-sequencing (RNA-seq), and a Cox proportional hazards model was applied to determine association with progression-free survival (PFS).Results:Confirmed response rates, median PFS, and median overall survival (OS) were higher in BM1 subtype patients compared with BM2 subtype patients. Evaluation of immune contexture identified greater immune reactivity in BM1, whereas cell-cycle signatures were more highly expressed in BM2. A multivariate model of PFS incorporating BM subtype plus immune and cell-cycle signatures revealed that BM subtype encompasses the majority of the effect.Conclusions:BM subtype is significantly associated with the outcome of combination dabrafenib, trametinib, and panitumumab therapy and may serve as a standalone predictive biomarker beyond mutational status. Our findings support a more nuanced approach to targeted therapeutic decisions that incorporates assessment of transcriptional context.
- Published
- 2023
6. Supplementary Data from BRAF-Mutant Transcriptional Subtypes Predict Outcome of Combined BRAF, MEK, and EGFR Blockade with Dabrafenib, Trametinib, and Panitumumab in Patients with Colorectal Cancer
- Author
-
Ryan B. Corcoran, Eduard Gasal, Fatima Rangwala, Jan C. Brase, John M. Millholland, Eric Van Cutsem, Filip De Vos, Peter J. O'Dwyer, Rona Yaeger, Josep Tabernero, Michael S. Gordon, Salvatore Siena, Autumn J. McRee, Antoine Hollebecque, Johanna C. Bendell, Takayuki Yoshino, Jan H.M. Schellens, Chloe E. Atreya, Thierry André, Catarina D. Campbell, Yiqun Yang, and Gary Middleton
- Abstract
Supplementary Data
- Published
- 2023
7. Data from Role of Tumor-Infiltrating B Cells in Clinical Outcome of Patients with Melanoma Treated With Dabrafenib Plus Trametinib
- Author
-
Alexander Roesch, Dirk Schadendorf, Eduard Gasal, Elisabeth Livingstone, Lisa Zimmer, Kurt W. Schmid, Antje Sucker, Jacob Schachter, Boguslawa Karaszewska, Keith T. Flaherty, Antoni Ribas, Paul D. Nathan, Georgina V. Long, Caroline Robert, Ken Schultz, Naveen Dakappagari, Ju Kim, Deborah Castelletti, Renata Varaljai, Tobias Schimming, James Garrett, Daniel Gusenleitner, Alexander Savchenko, Robert F.H. Walter, and Jan C. Brase
- Abstract
Purpose:Although patients with unresectable or metastatic melanoma can experience long-term survival with BRAF- and MEK-targeted agents or immune checkpoint inhibitors over 5 years, resistance develops in most patients. There is a distinct lack of pretherapeutic biomarkers to identify which patients are likely to benefit from each therapy type. Most research has focused on the predictive role of T cells in antitumor responses as opposed to B cells.Patients and Methods:We conducted prespecified exploratory biomarker analysis using gene expression profiling and digital pathology in 146 patients with previously untreated BRAF V600–mutant metastatic melanoma from the randomized, phase III COMBI-v trial and treated with dabrafenib plus trametinib who had available tumor specimens from screening.Results:Baseline cell-cycle gene expression signature was associated with progression-free survival (P = 0.007). Patients with high T-cell/low B-cell gene signatures had improved median overall survival (not reached [95% confidence interval (CI), 33.8 months–not reached]) compared with patients with high T-cell/high B-cell signatures (19.1 months; 95% CI, 13.4–38.6 months). Patients with high B-cell signatures had high B-cell infiltration into the tumor compartment, corresponding with decreased MAPK activity and increased expression of immunosuppressive markers.Conclusions:B cells may serve as a potential biomarker to predict clinical outcome in patients with advanced melanoma treated with dabrafenib plus trametinib. As separate studies have shown an opposite effect for B-cell levels and response to immunotherapy, B cells may serve as a potential biomarker to facilitate treatment selection. Further validation in a larger patient cohort is needed.
- Published
- 2023
8. Supplementary Data from Role of Tumor-Infiltrating B Cells in Clinical Outcome of Patients with Melanoma Treated With Dabrafenib Plus Trametinib
- Author
-
Alexander Roesch, Dirk Schadendorf, Eduard Gasal, Elisabeth Livingstone, Lisa Zimmer, Kurt W. Schmid, Antje Sucker, Jacob Schachter, Boguslawa Karaszewska, Keith T. Flaherty, Antoni Ribas, Paul D. Nathan, Georgina V. Long, Caroline Robert, Ken Schultz, Naveen Dakappagari, Ju Kim, Deborah Castelletti, Renata Varaljai, Tobias Schimming, James Garrett, Daniel Gusenleitner, Alexander Savchenko, Robert F.H. Walter, and Jan C. Brase
- Abstract
Supplementary Data from Role of Tumor-Infiltrating B Cells in Clinical Outcome of Patients with Melanoma Treated With Dabrafenib Plus Trametinib
- Published
- 2023
9. Data from Efficacy and Safety of Dabrafenib in Pediatric Patients with BRAF V600 Mutation–Positive Relapsed or Refractory Low-Grade Glioma: Results from a Phase I/IIa Study
- Author
-
Mark W. Kieran, James A. Whitlock, Eduard Gasal, Kohinoor Dasgupta, Lillian Tseng, Mark W. Russo, Ira J. Dunkel, Pooja Hingorani, Birgit Geoerger, Jordan R. Hansford, Kenneth J. Cohen, Alberto Broniscer, Uri Tabori, Eric Bouffet, and Darren R. Hargrave
- Abstract
Purpose:Pediatric low-grade glioma (pLGG) is the most prevalent childhood brain tumor. Patients with BRAF V600 mutation–positive pLGG may benefit from treatment with dabrafenib. Part 2 of a phase I/IIa study, open-label study (NCT01677741) explores the activity and safety of dabrafenib treatment in these patients.Patients and Methods:Patients ages 1 to BRAF V600–mutant solid tumors (≥1 evaluable lesion) with recurrent, refractory, or progressive disease after ≥1 standard therapy were treated with oral dabrafenib 3.0 to 5.25 mg/kg/day (part 1) or at the recommended phase II dose (RP2D; part 2). Primary objectives were to determine the RP2D (part 1, results presented in a companion paper) and assess clinical activity (part 2). Here, we report the clinical activity, including objective response rates (ORRs) using Response Assessment in Neuro-Oncology criteria and safety across parts 1 and 2.Results:Overall, 32 patients with pLGG were enrolled (part 1, n = 15; part 2, n = 17). Minimum follow-up was 26.2 months. Among all patients, the ORR was 44% [95% confidence interval (CI), 26–62] by independent review. The 1-year progression-free survival rate was 85% (95% CI, 64–94). Treatment-related adverse events (AE) were reported in 29 patients (91%); the most common was fatigue (34%). Grade 3/4 treatment-related AEs were reported in 9 patients (28%).Conclusions:Dabrafenib demonstrated meaningful clinical activity and acceptable tolerability in patients with BRAF V600–mutant pLGG.
- Published
- 2023
10. Figure S2 from Efficacy and Safety of Dabrafenib in Pediatric Patients with BRAF V600 Mutation–Positive Relapsed or Refractory Low-Grade Glioma: Results from a Phase I/IIa Study
- Author
-
Mark W. Kieran, James A. Whitlock, Eduard Gasal, Kohinoor Dasgupta, Lillian Tseng, Mark W. Russo, Ira J. Dunkel, Pooja Hingorani, Birgit Geoerger, Jordan R. Hansford, Kenneth J. Cohen, Alberto Broniscer, Uri Tabori, Eric Bouffet, and Darren R. Hargrave
- Abstract
Investigator-assessed percent change at maximum reduction from baseline in tumor measurement per RANO criteria
- Published
- 2023
11. Dabrafenib plus trametinib in patients with relapsed/refractory BRAF V600E mutation–positive hairy cell leukemia
- Author
-
Robert J. Kreitman, Philippe Moreau, Farhad Ravandi, Martin Hutchings, Anas Gazzah, Anne-Sophie Michallet, Zev A. Wainberg, Alexander Stein, Sascha Dietrich, Maja J. A. de Jonge, Wolfgang Willenbacher, Jacques De Grève, Evgeny Arons, Palanichamy Ilankumaran, Paul Burgess, Eduard Gasal, Vivek Subbiah, Medical Oncology, Medical Genetics, Clinical sciences, and Laboratory for Medical and Molecular Oncology
- Subjects
trametinib ,oncogenic driver mutation ,SDG 3 - Good Health and Well-being ,BRAF V600E ,Dabrafenib ,Immunology ,oncology ,relapsed/refractory BRAF V600E ,positive hairy cell leukemia ,Cell Biology ,Hematology ,HCl ,Biochemistry - Abstract
BRAF V600E is the key oncogenic driver mutation in hairy cell leukemia (HCL). We report the efficacy and safety of dabrafenib plus trametinib in patients with relapsed/refractory BRAF V600E mutation–positive HCL. This open-label, phase 2 study enrolled patients with BRAF V600E mutation–positive HCL refractory to first-line treatment with a purine analog or relapsed after ≥2 prior lines of treatment. Patients received dabrafenib 150 mg twice daily plus trametinib 2 mg once daily until disease progression, unacceptable toxicity, or death. The primary endpoint was investigator-assessed objective response rate (ORR) per criteria adapted from National Comprehensive Cancer Network-Consensus Resolution guidelines. Secondary endpoints included duration of response (DOR), progression-free survival (PFS), overall survival (OS), and safety. Fifty-five patients with BRAF V600E mutation–positive HCL were enrolled. The investigator-assessed ORR was 89.0% (95% confidence interval, 77.8%-95.9%); 65.5% of patients had a complete response (without minimal residual disease [MRD]: 9.1% [negative immunohistochemistry of bone marrow {BM} biopsy], 12.7% [negative BM aspirate flow cytometry {FC}], 16.4% [negative immunohistochemistry and/or FC results]; with MRD, 49.1%), and 23.6% had a partial response. The 24-month DOR was 97.7% with 24-month PFS and OS rates of 94.4% and 94.5%, respectively. The most common treatment-related adverse events were pyrexia (58.2%), chills (47.3%), and hyperglycemia (40.0%). Dabrafenib plus trametinib demonstrated durable responses with a manageable safety profile consistent with previous observations in other indications and should be considered as a rituximab-free therapeutic option for patients with relapsed/refractory BRAF V600E mutation–positive HCL. This trial is registered at www.clinicaltrials.gov as #NCT02034110.
- Published
- 2023
12. KEYNOTE-022: Pembrolizumab with trametinib in patients with BRAF wild-type melanoma or advanced solid tumours irrespective of BRAF mutation
- Author
-
Scott J. Diede, Michele Del Vecchio, Pier Francesco Ferrucci, Razi Ghori, Wilson H. Miller, Omid Hamid, Paolo A. Ascierto, Marcus O. Butler, Matteo S. Carlino, Antoni Ribas, Eduard Gasal, Elaine McWhirter, Robert Zielinski, Elizabeth Croydon, Michele Maio, and Anthony M. Joshua
- Subjects
Adult ,Male ,Proto-Oncogene Proteins B-raf ,Oncology ,Cancer Research ,medicine.medical_specialty ,Pyridones ,Pyrimidinones ,Pembrolizumab ,Antibodies, Monoclonal, Humanized ,Internal medicine ,Antineoplastic Combined Chemotherapy Protocols ,medicine ,Humans ,In patient ,Dosing ,Adverse effect ,Melanoma ,Objective response ,Aged ,Aged, 80 and over ,Trametinib ,business.industry ,Middle Aged ,medicine.disease ,Maximum tolerated dose ,Mutation ,Female ,business - Abstract
OBJECTIVES Parts 4 and 5 of the phase 1/2 KEYNOTE-022 study investigated the maximum tolerated dose (MTD), safety, and efficacy of pembrolizumab plus trametinib in solid tumours and BRAF wild-type melanoma. PATIENTS AND METHODS Patients received intermittent or concurrent dosing of pembrolizumab plus trametinib. Concurrent dosing was 2 or 4 weeks of trametinib run-in followed by concurrent pembrolizumab every 3 weeks (Q3W) plus trametinib once daily (QD). Intermittent dosing was 2 weeks of trametinib run-in followed by pembrolizumab plus intermittent trametinib (1 week off/2 weeks on). A 3 + 3 dose escalation was used, followed by dose confirmation. RESULTS Forty-two patients were enrolled. No dose-limiting toxicities (DLTs) occurred at initial dose levels (DL). At subsequent DLs, 10 of 38 evaluable patients had DLTs. For concurrent dosing, MTD was pembrolizumab 200 mg Q3W plus trametinib 1.5 mg QD, with a 2-week trametinib 1.5 mg QD run-in (concurrent DL2a); in concurrent DL2a group, five (31%) patients had grade 3/4 treatment-related adverse events (TRAEs); the objective response rate (ORR) was 0%. ORR was 40% in concurrent DL1 and 0% in concurrent DL2b. For intermittent dosing, MTD was pembrolizumab 200 mg Q3W plus trametinib 2 mg QD with a 2-week trametinib 2 mg QD run-in (intermittent DL2); in the intermittent DL2 group, seven (47%) patients had grade 3/4 TRAEs; ORR was 27%. ORR in intermittent DL1 was 33%. CONCLUSIONS MTDs for concurrent and intermittent dosing of pembrolizumab with trametinib were identified. The combination had limited antitumour activity, numerically higher ORR with intermittent versus concurrent dosing, and manageable safety. CLINICALTRIALS. GOV IDENTIFIER NCT02130466.
- Published
- 2022
13. Evaluation of the Effects of Repeat‐Dose Dabrafenib on the Single‐Dose Pharmacokinetics of Rosuvastatin (OATP1B1/1B3 Substrate) and Midazolam (CYP3A4 Substrate)
- Author
-
Victor Moreno, Noelia Nebot, Emmanuel Bouillaud, Dung-Yang Lee, Eva Muñoz-Couselo, Christina S. Won, Eduard Gasal, Institut Català de la Salut, [Nebot N, Lee DY, Gasal E] Novartis Pharmaceuticals Corporation, East Hanover, New Jersey, USA. [Won CS] Novartis Institutes for BioMedical Research, East Hanover, New Jersey, USA. [Moreno V] START Madrid-FJD, Hospital Universitario Fundación Jiménez Díaz, Madrid, Spain. [Muñoz-Couselo E] Vall d’Hebron Institute of Oncology (VHIO), Barcelona, Spain. Vall d’Hebron Hospital Universitari, Barcelona, Spain. [Bouillaud E] Novartis Pharma AG, Basel, Switzerland, and Vall d'Hebron Barcelona Hospital Campus
- Subjects
Male ,CYP3A4 ,CYP3A ,Pharmaceutical Science ,Pharmacology ,030226 pharmacology & pharmacy ,fenómenos fisiológicos::fenómenos farmacológicos y toxicológicos::fenómenos farmacológicos::interacciones farmacológicas [FENÓMENOS Y PROCESOS] ,0302 clinical medicine ,Oximes ,Medicine ,fenómenos fisiológicos::fenómenos farmacológicos y toxicológicos::farmacocinética [FENÓMENOS Y PROCESOS] ,Cytochrome P-450 CYP3A ,Pharmacology (medical) ,Drug Interactions ,Rosuvastatin Calcium ,OATP ,Liver-Specific Organic Anion Transporter 1 ,Imidazoles ,Articles ,Middle Aged ,Other subheadings::/pharmacology [Other subheadings] ,Physiological Phenomena::Pharmacological and Toxicological Phenomena::Pharmacokinetics [PHENOMENA AND PROCESSES] ,030220 oncology & carcinogenesis ,Area Under Curve ,Female ,pharmacokinetics ,medicine.drug ,Adult ,Midazolam ,Cmax ,Original Manuscript ,transporters ,Chemical Actions and Uses::Pharmacologic Actions::Molecular Mechanisms of Pharmacological Action::Enzyme Inhibitors::Protein Kinase Inhibitors [CHEMICALS AND DRUGS] ,03 medical and health sciences ,Solute Carrier Organic Anion Transporter Family Member 1B3 ,Pharmacokinetics ,Humans ,Rosuvastatin ,dabrafenib ,Protein Kinase Inhibitors ,drug interaction ,Farmacocinètica ,business.industry ,acciones y usos químicos::acciones farmacológicas::mecanismos moleculares de acción farmacológica::inhibidores enzimáticos::inhibidores de proteínas cinasas [COMPUESTOS QUÍMICOS Y DROGAS] ,Dabrafenib ,Drug interaction ,Medicaments - Interacció ,Proteïnes quinases - Inhibidors ,Physiological Phenomena::Pharmacological and Toxicological Phenomena::Pharmacological Phenomena::Drug Interactions [PHENOMENA AND PROCESSES] ,Otros calificadores::/farmacología [Otros calificadores] ,business - Abstract
Dabrafenib; Drug interaction; Pharmacokinetics Dabrafenib; Interacción de fármacos; Farmacocinética Dabrafenib; Interacció de fàrmacs; Farmacocinètica Dabrafenib is an oral BRAF kinase inhibitor approved for the treatment of various BRAF V600 mutation–positive solid tumors. In vitro observations suggesting cytochrome P450 (CYP) 3A induction and organic anion transporting polypeptide (OATP) inhibition prompted us to evaluate the effect of dabrafenib 150 mg twice daily on the pharmacokinetics of midazolam 3 mg (CYP3A substrate) and rosuvastatin 10 mg (OATP1B1/1B3 substrate) in a clinical phase 1, open-label, fixed-sequence study in patients with BRAF V600 mutation–positive tumors. Repeat dabrafenib dosing resulted in a 2.56-fold increase in rosuvastatin maximum observed concentration (Cmax), an earlier time to Cmax, but only a 7% increase in area under the concentration-time curve from time 0 (predose) extrapolated to infinite time. Midazolam Cmax and AUC extrapolated to infinite time decreased by 47% and 65%, respectively, with little effect on time to Cmax. No new safety findings were reported. Exposure of drugs that are CYP3A4 substrates is likely to decrease when coadministered with dabrafenib. Concentrations of medicinal products that are sensitive OATP1B1/1B3 substrates may increase during the absorption phase. This study was sponsored by GlaxoSmithKline; dabrafenib and trametinib are assets of Novartis AG as of March 2, 2015.
- Published
- 2021
14. Spartalizumab or placebo in combination with dabrafenib and trametinib in patients with BRAF V600-mutant melanoma: exploratory biomarker analyses from a randomized phase 3 trial (COMBI-i)
- Author
-
Hussein A Tawbi, Caroline Robert, Jan C Brase, Daniel Gusenleitner, Eduard Gasal, James Garrett, Alexander Savchenko, Güllü Görgün, Keith T Flaherty, Antoni Ribas, Reinhard Dummer, Dirk Schadendorf, Georgina V Long, Paul D Nathan, and Paolo A Ascierto
- Subjects
Proto-Oncogene Proteins B-raf ,Cancer Research ,Skin Neoplasms ,Pyridones ,Immunology ,Clinical Trials and Supportive Activities ,Medizin ,Pyrimidinones ,Antibodies ,B7-H1 Antigen ,Drug Therapy ,Clinical Research ,Oximes ,Antineoplastic Combined Chemotherapy Protocols ,Monoclonal ,Genetics ,Immunology and Allergy ,Humans ,Clinical Trials ,Melanoma ,Humanized ,Randomized Controlled Trials as Topic ,Tumor Biomarkers ,Cancer ,Pharmacology ,Tumor ,Imidazoles ,Evaluation of treatments and therapeutic interventions ,Phase III as Topic ,Good Health and Well Being ,Oncology ,6.1 Pharmaceuticals ,Combination ,Molecular Medicine ,Biomarkers - Abstract
BackgroundThe randomized phase 3 COMBI-i trial did not meet its primary endpoint of improved progression-free survival (PFS) with spartalizumab plus dabrafenib and trametinib (sparta-DabTram) vs placebo plus dabrafenib and trametinib (placebo-DabTram) in the overall population of patients with unresectable/metastatic BRAF V600-mutant melanoma. This prespecified exploratory biomarker analysis was performed to identify subgroups that may derive greater treatment benefit from sparta-DabTram.MethodsIn COMBI-i (ClinicalTrials.gov, NCT02967692), 532 patients received spartalizumab 400 mg intravenously every 4 weeks plus dabrafenib 150 mg orally two times daily and trametinib 2 mg orally one time daily or placebo-DabTram. Baseline/on-treatment pharmacodynamic markers were assessed via flow cytometry-based immunophenotyping and plasma cytokine profiling. Baseline programmed death ligand 1 (PD-L1) status and T-cell phenotype were assessed via immunohistochemistry; BRAF V600 mutation type, tumor mutational burden (TMB), and circulating tumor DNA (ctDNA) via DNA sequencing; gene expression signatures via RNA sequencing; and CD4+/CD8+ T-cell ratio via immunophenotyping.ResultsExtensive biomarker analyses were possible in approximately 64% to 90% of the intention-to-treat population, depending on sample availability and assay. Subgroups based on PD-L1 status/TMB or T-cell inflammation did not show significant differences in PFS benefit with sparta-DabTram vs placebo-DabTram, although T-cell inflammation was prognostic across treatment arms. Subgroups defined by BRAF V600K mutation (HR 0.45 (95% CI 0.21 to 0.99)), detectable ctDNA shedding (HR 0.75 (95% CI 0.58 to 0.96)), or CD4+/CD8+ ratio above median (HR 0.58 (95% CI 0.40 to 0.84)) derived greater PFS benefit with sparta-DabTram vs placebo-DabTram. In a multivariate analysis, ctDNA emerged as strongly prognostic (p=0.007), while its predictive trend did not reach significance; in contrast, CD4+/CD8+ ratio was strongly predictive (interaction p=0.0131).ConclusionsThese results support the feasibility of large-scale comprehensive biomarker analyses in the context of a global phase 3 study. T-cell inflammation was prognostic but not predictive of sparta-DabTram benefit, as patients with high T-cell inflammation already benefit from targeted therapy alone. Baseline ctDNA shedding also emerged as a strong independent prognostic variable, with predictive trends consistent with established measures of disease burden such as lactate dehydrogenase levels. CD4+/CD8+ T-cell ratio was significantly predictive of PFS benefit with sparta-DabTram but requires further validation as a biomarker in melanoma. Taken together with previous observations, further study of checkpoint inhibitor plus targeted therapy combination in patients with higher disease burden may be warranted.Trial registration numberNCT02967692.
- Published
- 2022
15. Randomized Phase III Trial Evaluating Spartalizumab Plus Dabrafenib and Trametinib for BRAF V600–Mutant Unresectable or Metastatic Melanoma
- Author
-
Reinhard Dummer, Georgina V. Long, Caroline Robert, Hussein A. Tawbi, Keith T. Flaherty, Paolo A. Ascierto, Paul D. Nathan, Piotr Rutkowski, Oleg Leonov, Caroline Dutriaux, Mario Mandalà, Paul Lorigan, Pier Francesco Ferrucci, Jean Jacques Grob, Nicolas Meyer, Helen Gogas, Daniil Stroyakovskiy, Ana Arance, Jan C. Brase, Steven Green, Tomas Haas, Aisha Masood, Eduard Gasal, Antoni Ribas, Dirk Schadendorf, and University of Zurich
- Subjects
Proto-Oncogene Proteins B-raf ,Adult ,Cancer Research ,Skin Neoplasms ,Adolescent ,Pyridones ,Clinical Trials and Supportive Activities ,Clinical Sciences ,Oncology and Carcinogenesis ,Medizin ,610 Medicine & health ,Pyrimidinones ,Antibodies ,Death Domain ,Clinical Research ,Neoplasms ,Oximes ,Antineoplastic Combined Chemotherapy Protocols ,Receptors ,Monoclonal ,Genetics ,Humans ,Oncology & Carcinogenesis ,Melanoma ,Humanized ,Cancer ,Manchester Cancer Research Centre ,ResearchInstitutes_Networks_Beacons/mcrc ,Human Genome ,Imidazoles ,Evaluation of treatments and therapeutic interventions ,10177 Dermatology Clinic ,Second Primary ,Oncology ,6.1 Pharmaceuticals ,Mutation - Abstract
PURPOSEPreclinical data suggest the combination of an anti–programmed death receptor 1 antibody plus dabrafenib and trametinib to have superior antitumor activity compared with dabrafenib plus trametinib alone. These observations are supported by translational evidence suggesting that immune checkpoint inhibitors plus targeted therapy may improve treatment outcomes in patients with BRAF V600–mutant metastatic melanoma. COMBI-i is a phase III trial evaluating spartalizumab, an anti–programmed death receptor 1 antibody, in combination with dabrafenib and trametinib (sparta-DabTram), versus placebo plus dabrafenib and trametinib (placebo-DabTram) in patients with BRAF V600–mutant unresectable or metastatic melanoma.METHODSPatients received spartalizumab 400 mg intravenously every 4 weeks plus dabrafenib 150 mg orally twice daily and trametinib 2 mg orally once daily or placebo-DabTram. Participants were age ≥ 18 years with unresectable or metastatic BRAF V600–mutant melanoma. The primary end point was investigator-assessed progression-free survival. Overall survival was a key secondary end point (ClinicalTrials.gov identifier: NCT02967692 ).RESULTSAt data cutoff (July 1, 2020), the median progression-free survival was 16.2 months (95% CI, 12.7 to 23.9 months) in the sparta-DabTram arm versus 12.0 months (95% CI, 10.2 to 15.4 months) in the placebo-DabTram arm (hazard ratio, 0.82 [95% CI, 0.66 to 1.03]; P = .042 [one-sided; nonsignificant]). The objective response rates were 69% (183 of 267 patients) versus 64% (170 of 265 patients), respectively. Grade ≥ 3 treatment-related adverse events occurred in 55% (146 of 267) of patients in the sparta-DabTram arm and 33% (88 of 264) in the placebo-DabTram arm.CONCLUSIONThe study did not meet its primary end point; broad first-line use of sparta-DabTram is not supported by these results. Further biomarker-driven investigation may identify patient subpopulations who could benefit from checkpoint inhibitor plus targeted therapy combinations.
- Published
- 2022
16. Dabrafenib plus trametinib in patients with BRAFV600E-mutant low-grade and high-grade glioma (ROAR): a multicentre, open-label, single-arm, phase 2, basket trial
- Author
-
Jean-Yves Blay, Angelica Fasolo, Palanichamy Ilankumaran, Tae Min Kim, Daniel C Cho, Jeffrey Yachnin, Filip de Vos, Martin J. van den Bent, Eduard Gasal, Albert Lai, Antje Wick, Mario Campone, Damien Pouessel, Myra E. van Linde, Alexander Stein, Jacques De Greve, Warren P. Mason, Jose A. Lopez-Martin, Anas Gazzah, Nikolas von Bubnoff, Vivek Subbiah, Gerald W. Prager, Ralf-Dieter Hofheinz, Patrick Y. Wen, Aislyn Boran, Paul Burgess, Neurology, Internal medicine, CCA - Cancer Treatment and quality of life, Medical Genetics, Clinical sciences, and Laboratory for Medical and Molecular Oncology
- Subjects
Adult ,Male ,Oncology ,medicine.medical_specialty ,Adolescent ,Neuroscience(all) ,Population ,Oximes/administration & dosage ,Brain Neoplasms/drug therapy ,Isocitrate Dehydrogenase/genetics ,Neutropenia ,SDG 3 - Good Health and Well-being ,Internal medicine ,Glioma ,Proto-Oncogene Proteins B-raf/genetics ,Internal Medicine ,medicine ,Clinical endpoint ,Humans ,education ,Aged ,Trametinib ,education.field_of_study ,Pyridones/administration & dosage ,business.industry ,Antineoplastic Combined Chemotherapy Protocols/adverse effects ,neurology ,Dabrafenib ,Middle Aged ,Interim analysis ,medicine.disease ,Glioma/drug therapy ,Cohort ,young adult ,Female ,Pyrimidinones/administration & dosage ,mutation ,business ,Imidazoles/administration & dosage ,medicine.drug - Abstract
Background: Effective treatments are needed to improve outcomes for high-grade glioma and low-grade glioma. The activity and safety of dabrafenib plus trametinib were evaluated in adult patients with recurrent or progressive BRAFV600E mutation-positive high-grade glioma and low-grade glioma. Methods: This study is part of an ongoing open-label, single-arm, phase 2 Rare Oncology Agnostic Research (ROAR) basket trial at 27 community and academic cancer centres in 13 countries (Austria, Belgium, Canada, France, Germany, Italy, Japan, the Netherlands, Norway, South Korea, Spain, Sweden, and the USA). The study enrolled patients aged 18 years or older with an Eastern Cooperative Oncology Group performance status of 0, 1, or 2. Patients with BRAFV600E mutation-positive high-grade glioma and low-grade glioma received dabrafenib 150 mg twice daily plus trametinib 2 mg once daily orally until unacceptable toxicity, disease progression, or death. In the high-grade glioma cohort, patients were required to have measurable disease at baseline using the Response Assessment in Neuro-Oncology high-grade glioma response criteria and have been treated previously with radiotherapy and first-line chemotherapy or concurrent chemoradiotherapy. Patients with low-grade glioma were required to have measurable non-enhancing disease (except pilocytic astrocytoma) at baseline using the Response Assessment in Neuro-Oncology low-grade glioma criteria. The primary endpoint, in the evaluable intention-to-treat population, was investigator-assessed objective response rate (complete response plus partial response for high-grade glioma and complete response plus partial response plus minor response for low-grade glioma). This trial is ongoing, but is closed for enrolment, NCT02034110. Findings: Between April 17, 2014, and July 25, 2018, 45 patients (31 with glioblastoma) were enrolled into the high-grade glioma cohort and 13 patients were enrolled into the low-grade glioma cohort. The results presented here are based on interim analysis 16 (data cutoff Sept 14, 2020). In the high-grade glioma cohort, median follow-up was 12·7 months (IQR 5·4–32·3) and 15 (33%; 95% CI 20–49) of 45 patients had an objective response by investigator assessment, including three complete responses and 12 partial responses. In the low-grade glioma cohort, median follow-up was 32·2 months (IQR 25·1–47·8). Nine (69%; 95% CI 39–91) of 13 patients had an objective response by investigator assessment, including one complete response, six partial responses, and two minor responses. Grade 3 or worse adverse events were reported in 31 (53%) patients, the most common being fatigue (five [9%]), decreased neutrophil count (five [9%]), headache (three [5%]), and neutropenia (three [5%]). Interpretation: Dabrafenib plus trametinib showed clinically meaningful activity in patients with BRAFV600E mutation-positive recurrent or refractory high-grade glioma and low-grade glioma, with a safety profile consistent with that in other indications. BRAFV600E testing could potentially be adopted in clinical practice for patients with glioma. Funding: Novartis.
- Published
- 2022
17. Phase 2 Study of Dabrafenib Plus Trametinib in Patients With BRAF V600E-Mutant Metastatic NSCLC: Updated 5-year survival rates and genomic analysis
- Author
-
Harry J.M. Groen, David Planchard, Benjamin Besse, Elisabeth Quoix, Eduard Gasal, Bruce E. Johnson, Ronan J. Kelly, Julien Mazieres, Libero Santarpia, Sayed M S Hashemi, Shirong Zhang, Liza C. Villaruz, Pierre Jean Souquet, Fabrice Barlesi, Christina S. Baik, Tae Min Kim, Monique Tan, Pulmonary medicine, CCA - Cancer Treatment and quality of life, Guided Treatment in Optimal Selected Cancer Patients (GUTS), and Damage and Repair in Cancer Development and Cancer Treatment (DARE)
- Subjects
Proto-Oncogene Proteins B-raf ,Pulmonary and Respiratory Medicine ,Oncology ,medicine.medical_specialty ,Lung Neoplasms ,Pyridones ,CELL LUNG-CANCER ,MULTICENTER ,Phases of clinical research ,MELANOMA ,Pyrimidinones ,Genomic analysis ,Non-small cell lung cancer ,Trametinib ,Internal medicine ,Antineoplastic Combined Chemotherapy Protocols ,Oximes ,medicine ,Clinical endpoint ,Humans ,CRIZOTINIB ,Adverse effect ,Survival analysis ,BRAF V600E ,MUTATIONS ,business.industry ,Dabrafenib ,Imidazoles ,Genomics ,CHEMOTHERAPY ,OPEN-LABEL ,Survival Rate ,COMBINATION THERAPY ,1ST-LINE TREATMENT ,Response Evaluation Criteria in Solid Tumors ,Mutation ,Cohort ,business ,RESISTANCE ,medicine.drug - Abstract
INTRODUCTION: Dabrafenib plus trametinib was found to have robust antitumor activity in patients with BRAF V600E-mutant metastatic NSCLC (mNSCLC). We report updated survival analysis of a phase 2 study (NCT01336634) with a minimum of 5-year follow-up and updated genomic data.METHODS: Pretreated (cohort B) and treatment-naive (cohort C) patients with BRAF V600E-mutant mNSCLC received dabrafenib 150 mg twice daily and trametinib 2 mg once daily. The primary end point was investigator-assessed overall response rate per Response Evaluation Criteria in Solid Tumors version 1.1. Secondary end points were duration of response, progression-free survival, overall survival, and safety.RESULTS: At data cutoff, for cohorts B (57 patients) and C (36 patients), the median follow-up was 16.6 (range: 0.5-78.5) and 16.3 (range: 0.4-80) months, overall response rate (95% confidence interval [CI]) was 68.4% (54.8-80.1) and 63.9% (46.2-79.2), median progression-free survival (95% CI) was 10.2 (6.9-16.7) and 10.8 (7.0-14.5) months, and median overall survival (95% CI) was 18.2 (14.3-28.6) and 17.3 (12.3-40.2) months, respectively. The 4- and 5-year survival rates were 26% and 19% in pretreated patients and 34% and 22% in treatment-naive patients, respectively. A total of 17 patients (18%) were still alive. The most frequent adverse event was pyrexia (56%). Exploratory genomic analysis indicated that the presence of coexisting genomic alterations might influence clinical outcomes in these patients; however, these results require further investigation.CONCLUSIONS: Dabrafenib plus trametinib therapy was found to have substantial and durable clinical benefit, with a manageable safety profile, in patients with BRAF V600E-mutant mNSCLC, regardless of previous treatment.
- Published
- 2022
18. Dabrafenib plus trametinib in patients with BRAFV600E-mutated biliary tract cancer (ROAR): a phase 2, open-label, single-arm, multicentre basket trial
- Author
-
Angelica Fasolo, Antoine Italiano, Kert Viele, Gerald W. Prager, Richard Greil, Vivek Subbiah, Milind Javle, Patrick Y. Wen, Eduard Gasal, Giuseppe Curigliano, Jan H.M. Schellens, Aislyn Boran, Palanichamy Ilankumaran, Alexander Stein, Ulrik Lassen, Paul Burgess, Elena Elez, Filippo de Braud, and Zev A. Wainberg
- Subjects
0301 basic medicine ,Trametinib ,education.field_of_study ,medicine.medical_specialty ,Biliary tract neoplasm ,business.industry ,Population ,Dabrafenib ,Interim analysis ,03 medical and health sciences ,030104 developmental biology ,0302 clinical medicine ,Oncology ,Response Evaluation Criteria in Solid Tumors ,030220 oncology & carcinogenesis ,Internal medicine ,medicine ,Clinical endpoint ,Progression-free survival ,education ,business ,medicine.drug - Abstract
Summary Background Effective treatments for patients with cholangiocarcinoma after progression on gemcitabine-based chemotherapy are urgently needed. Mutations in the BRAF gene have been found in 5% of biliary tract tumours. The combination of dabrafenib and trametinib has shown activity in several BRAFV600E-mutated cancers. We aimed to assess the activity and safety of dabrafenib and trametinib combination therapy in patients with BRAFV600E-mutated biliary tract cancer. Methods This study is part of an ongoing, phase 2, open-label, single-arm, multicentre, Rare Oncology Agnostic Research (ROAR) basket trial in patients with BRAFV600E-mutated rare cancers. Patients were eligible for the biliary tract cancer cohort if they were aged 18 years or older, had BRAFV600E-mutated, unresectable, metastatic, locally advanced, or recurrent biliary tract cancer, an Eastern Cooperative Oncology Group performance status of 0–2, and had received previous systemic treatment. All patients were treated with oral dabrafenib 150 mg twice daily and oral trametinib 2 mg once daily until disease progression or intolerance of treatment. The primary endpoint was the overall response rate, which was determined by Response Evaluation Criteria in Solid Tumors version 1.1 in the intention-to-treat evaluable population, which comprised all enrolled patients regardless of receiving treatment who were evaluable (ie, had progression, began a new anticancer treatment, withdrew consent, died, had stable disease for 6 weeks or longer, or had two or more post-baseline assessments). The ROAR trial is registered with ClinicalTrials.gov , NCT02034110 . These results are based on an interim analysis; the study is active but not recruiting. Findings Between March 12, 2014, and July 18, 2018, 43 patients with BRAFV600E-mutated biliary tract cancer were enrolled to the study and were evaluable. Median follow-up was 10 months (IQR 6–15). An investigator-assessed overall response was achieved by 22 (51%, 95% CI 36–67) of 43 patients. An independent reviewer-assessed overall response was achieved by 20 (47%, 95% CI 31–62) of 43 patients. The most common grade 3 or worse adverse event was increased γ-glutamyltransferase in five (12%) patients. 17 (40%) patients had serious adverse events and nine (21%) had treatment-related serious adverse events, the most frequent of which was pyrexia (eight [19%]). No treatment-related deaths were reported. Interpretation Dabrafenib plus trametinib combination treatment showed promising activity in patients with BRAFV600E-mutated biliary tract cancer, with a manageable safety profile. Routine testing for BRAFV600E mutations should be considered in patients with biliary tract cancer. Funding GlaxoSmithKline and Novartis.
- Published
- 2020
19. Open-label, phase IIa study of dabrafenib plus trametinib in East Asian patients with advanced BRAF V600-mutant cutaneous melanoma
- Author
-
Xiaoshi Zhang, Lu Si, Dung Yang Lee, Tae Min Kim, Jun Guo, Haifu Li, Yun Fan, Arunee Dechaphunkul, Jedzada Maneechavakajorn, Chia-Chi Lin, Sang Joon Shin, Palanichamy Ilankumaran, Chi Sing Wong, and Eduard Gasal
- Subjects
Adult ,Male ,Proto-Oncogene Proteins B-raf ,0301 basic medicine ,Cancer Research ,medicine.medical_specialty ,Asia ,Skin Neoplasms ,Time Factors ,Pyridones ,Cmax ,Pyrimidinones ,Gastroenterology ,03 medical and health sciences ,0302 clinical medicine ,Internal medicine ,Antineoplastic Combined Chemotherapy Protocols ,Oximes ,Biomarkers, Tumor ,medicine ,Humans ,Adverse effect ,Melanoma ,Protein Kinase Inhibitors ,Aged ,Aged, 80 and over ,Trametinib ,business.industry ,Imidazoles ,Dabrafenib ,Middle Aged ,medicine.disease ,Progression-Free Survival ,Discontinuation ,030104 developmental biology ,Oncology ,Tolerability ,030220 oncology & carcinogenesis ,Mutation ,Cutaneous melanoma ,Female ,business ,medicine.drug - Abstract
Purpose This study (NCT02083354) assessed the efficacy and safety of dabrafenib plus trametinib in East Asian patients with advanced BRAF V600-mutant cutaneous melanoma. Method Overall, 77 patients of East Asian origin (including 61 from Mainland China) with unresectable or metastatic BRAF V600-mutant cutaneous melanoma were enrolled. Prior treatment was allowed except with BRAF/MEK inhibitors. Patients received dabrafenib 150 mg twice daily and trametinib 2 mg once daily. The primary end-point was objective response rate (ORR) using Response Evaluation Criteria in Solid Tumours 1.1. Secondary end-points were duration of response (DOR), progression-free survival (PFS), overall survival (OS), pharmacokinetics and safety. Results At data cutoff (February 23, 2018; median follow-up, 8.3 months), treatment was ongoing in 36 patients (47%). The median age was 52 years; 32% of patients had elevated lactate dehydrogenase, and 84% had received prior systemic therapy. ORR was 61% (95% confidence interval: 49.2–72.0), with four patients (5%) achieving complete response. Median DOR and PFS were 11.3 and 7.9 months, respectively. Median OS was not reached. The most common adverse event (AE) of any grade was pyrexia (56%). Grade ≥III AEs occurred in 29 patients (38%). The most common grade ≥III AEs were pyrexia (8%) and anaemia (6%). AEs led to permanent discontinuation in five patients (6.5%). Mean Cmax for dabrafenib and trametinib was 3560 and 11.5 ng/mL (day 1) and 2680 and 27.1 ng/mL (day 15), respectively. Conclusion These results support the efficacy and tolerability of dabrafenib in combination with trametinib in East Asian patients with unresectable or metastatic BRAF V600-mutant cutaneous melanoma.
- Published
- 2020
20. BRAF-Mutant Transcriptional Subtypes Predict Outcome of Combined BRAF, MEK, and EGFR Blockade with Dabrafenib, Trametinib, and Panitumumab in Patients with Colorectal Cancer
- Author
-
Autumn J. McRee, Takayuki Yoshino, Filip de Vos, Chloe E. Atreya, Eduard Gasal, Jan H.M. Schellens, Salvatore Siena, Eric Van Cutsem, Rona Yaeger, Thierry André, John Millholland, Ryan B. Corcoran, Antoine Hollebecque, Catarina D. Campbell, Josep Tabernero, Peter J. O'Dwyer, Fatima Rangwala, Johanna C. Bendell, Jan C. Brase, Yiqun Yang, Gary Middleton, and Michael S. Gordon
- Subjects
Proto-Oncogene Proteins B-raf ,0301 basic medicine ,Oncology ,Cancer Research ,medicine.medical_specialty ,Pyridones ,Colorectal cancer ,medicine.medical_treatment ,Oncology and Carcinogenesis ,MAP Kinase Kinase 1 ,Context (language use) ,Pyrimidinones ,Targeted therapy ,03 medical and health sciences ,0302 clinical medicine ,Clinical Research ,Internal medicine ,Oximes ,Antineoplastic Combined Chemotherapy Protocols ,Genetics ,medicine ,Humans ,Panitumumab ,Oncology & Carcinogenesis ,Cancer ,Trametinib ,Neoplastic ,Tumor ,business.industry ,Imidazoles ,Dabrafenib ,Cell cycle ,Prognosis ,medicine.disease ,Colo-Rectal Cancer ,Survival Rate ,ErbB Receptors ,030104 developmental biology ,Gene Expression Regulation ,030220 oncology & carcinogenesis ,Mutation ,Colorectal Neoplasms ,Digestive Diseases ,business ,Biomarkers ,medicine.drug - Abstract
Purpose: The influence of the transcriptional and immunologic context of mutations on therapeutic outcomes with targeted therapy in cancer has not been well defined. BRAF V600E–mutant (BM) colorectal cancer comprises two main transcriptional subtypes, BM1 and BM2. We sought to determine the impact of BM subtype, as well as distinct biological features of those subtypes, on response to BRAF/MEK/EGFR inhibition in patients with colorectal cancer. Patients and Methods: Paired fresh tumor biopsies were acquired at baseline and on day 15 of treatment from all consenting patients with BM colorectal cancer enrolled in a phase II clinical trial of dabrafenib, trametinib, and panitumumab. For each sample, BM subtype, cell cycle, and immune gene signature expression were determined using RNA-sequencing (RNA-seq), and a Cox proportional hazards model was applied to determine association with progression-free survival (PFS). Results: Confirmed response rates, median PFS, and median overall survival (OS) were higher in BM1 subtype patients compared with BM2 subtype patients. Evaluation of immune contexture identified greater immune reactivity in BM1, whereas cell-cycle signatures were more highly expressed in BM2. A multivariate model of PFS incorporating BM subtype plus immune and cell-cycle signatures revealed that BM subtype encompasses the majority of the effect. Conclusions: BM subtype is significantly associated with the outcome of combination dabrafenib, trametinib, and panitumumab therapy and may serve as a standalone predictive biomarker beyond mutational status. Our findings support a more nuanced approach to targeted therapeutic decisions that incorporates assessment of transcriptional context.
- Published
- 2020
21. Efficacy and Safety of Dabrafenib in Pediatric Patients with BRAF V600 Mutation–Positive Relapsed or Refractory Low-Grade Glioma: Results from a Phase I/IIa Study
- Author
-
Mark W. Kieran, Uri Tabori, Kohinoor Dasgupta, Eduard Gasal, Jordan R. Hansford, Eric Bouffet, Mark W. Russo, James A. Whitlock, Ira J. Dunkel, Pooja Hingorani, Darren Hargrave, Lillian Tseng, Alberto Broniscer, Birgit Geoerger, and Kenneth J. Cohen
- Subjects
0301 basic medicine ,Oncology ,Cancer Research ,medicine.medical_specialty ,business.industry ,Neurooncology ,Dabrafenib ,medicine.disease ,Clinical trial ,03 medical and health sciences ,030104 developmental biology ,0302 clinical medicine ,Tolerability ,030220 oncology & carcinogenesis ,Internal medicine ,Glioma ,medicine ,Progression-free survival ,business ,Adverse effect ,Survival rate ,medicine.drug - Abstract
Purpose: Pediatric low-grade glioma (pLGG) is the most prevalent childhood brain tumor. Patients with BRAF V600 mutation–positive pLGG may benefit from treatment with dabrafenib. Part 2 of a phase I/IIa study, open-label study (NCT01677741) explores the activity and safety of dabrafenib treatment in these patients. Patients and Methods: Patients ages 1 to Results: Overall, 32 patients with pLGG were enrolled (part 1, n = 15; part 2, n = 17). Minimum follow-up was 26.2 months. Among all patients, the ORR was 44% [95% confidence interval (CI), 26–62] by independent review. The 1-year progression-free survival rate was 85% (95% CI, 64–94). Treatment-related adverse events (AE) were reported in 29 patients (91%); the most common was fatigue (34%). Grade 3/4 treatment-related AEs were reported in 9 patients (28%). Conclusions: Dabrafenib demonstrated meaningful clinical activity and acceptable tolerability in patients with BRAF V600–mutant pLGG.
- Published
- 2019
22. Role of Tumor-Infiltrating B Cells in Clinical Outcome of Patients with Melanoma Treated With Dabrafenib Plus Trametinib
- Author
-
Boguslawa Karaszewska, Deborah Castelletti, Lisa Zimmer, Kurt Werner Schmid, Elisabeth Livingstone, Renáta Váraljai, Alexander Savchenko, Georgina V. Long, Paul Nathan, Caroline Robert, Jan C. Brase, Robert Fred Henry Walter, Ken Schultz, Eduard Gasal, Jacob Schachter, Daniel Gusenleitner, Antje Sucker, James Garrett, Tobias Schimming, Dirk Schadendorf, Antoni Ribas, Alexander Roesch, Ju Young Kim, Naveen Dakappagari, and Keith T. Flaherty
- Subjects
Oncology ,Cancer Research ,medicine.medical_specialty ,Skin Neoplasms ,Pyridones ,medicine.medical_treatment ,Clinical Trials and Supportive Activities ,Oncology and Carcinogenesis ,Medizin ,Pyrimidinones ,Clinical Research ,Internal medicine ,Antineoplastic Combined Chemotherapy Protocols ,Oximes ,Genetics ,medicine ,Humans ,Oncology & Carcinogenesis ,Biomarker Analysis ,Melanoma ,Cancer ,Trametinib ,screening and diagnosis ,B-Lymphocytes ,business.industry ,Imidazoles ,Dabrafenib ,Immunotherapy ,medicine.disease ,Confidence interval ,Gene expression profiling ,Detection ,Treatment Outcome ,Cohort ,business ,4.2 Evaluation of markers and technologies ,medicine.drug - Abstract
Purpose: Although patients with unresectable or metastatic melanoma can experience long-term survival with BRAF- and MEK-targeted agents or immune checkpoint inhibitors over 5 years, resistance develops in most patients. There is a distinct lack of pretherapeutic biomarkers to identify which patients are likely to benefit from each therapy type. Most research has focused on the predictive role of T cells in antitumor responses as opposed to B cells. Patients and Methods: We conducted prespecified exploratory biomarker analysis using gene expression profiling and digital pathology in 146 patients with previously untreated BRAF V600–mutant metastatic melanoma from the randomized, phase III COMBI-v trial and treated with dabrafenib plus trametinib who had available tumor specimens from screening. Results: Baseline cell-cycle gene expression signature was associated with progression-free survival (P = 0.007). Patients with high T-cell/low B-cell gene signatures had improved median overall survival (not reached [95% confidence interval (CI), 33.8 months–not reached]) compared with patients with high T-cell/high B-cell signatures (19.1 months; 95% CI, 13.4–38.6 months). Patients with high B-cell signatures had high B-cell infiltration into the tumor compartment, corresponding with decreased MAPK activity and increased expression of immunosuppressive markers. Conclusions: B cells may serve as a potential biomarker to predict clinical outcome in patients with advanced melanoma treated with dabrafenib plus trametinib. As separate studies have shown an opposite effect for B-cell levels and response to immunotherapy, B cells may serve as a potential biomarker to facilitate treatment selection. Further validation in a larger patient cohort is needed.
- Published
- 2020
23. P863 KEYNOTE-022 parts 4 and 5: pembrolizumab plus trametinib for patients with solid tumors or BRAF wild-type melanoma
- Author
-
Matteo S. Carlino, Paolo A. Ascierto, Omid Hamid, Wilson H. Miller, Razi Ghori, Robert Zielinski, Marcus W. Butler, Antoni Ribas, Pier Francesco Ferrucci, Elizabeth Croydon, Elaine McWhirter, Michele Del Vecchio, Eduard Gasal, Scott J. Diede, Michele Maio, and Anthony M. Joshua
- Subjects
Oncology ,Trametinib ,medicine.medical_specialty ,business.industry ,Melanoma ,Dabrafenib ,Pembrolizumab ,medicine.disease ,Placebo ,Discontinuation ,Tolerability ,Internal medicine ,medicine ,Dosing ,business ,medicine.drug - Abstract
Background Pembrolizumab+dabrafenib+trametinib demonstrated promising antitumor activity and acceptable tolerability in BRAF-mutant melanoma in phase 1/2 KEYNOTE-022 parts 1 and 2 (NCT02130466). Pembrolizumab+dabrafenib+trametinib numerically prolonged PFS and DOR versus placebo+dabrafenib+trametinib but had a higher grade 3-5 TRAE rate in part 3. KEYNOTE-022 parts 4 and 5 evaluated pembrolizumab+trametinib. Methods In part 4 (open-label, 3+3 dose-finding) patients with advanced solid tumors (irrespective of BRAF status) or unresectable/metastatic BRAF wild-type melanoma received pembrolizumab 200 mg Q3W with trametinib as concurrent (2 or 4 weeks of trametinib run-in [1.5 or 2 mg QD], then pembrolizumab+trametinib [1.5 or 2 mg QD]) or intermittent dosing (2 weeks of trametinib run-in [1.5 or 2 mg QD], then pembrolizumab+trametinib [1.5 or 2 mg QD; 1 week off/2 weeks on]). Interim MTDs identified in part 4 were confirmed in part 5 using a modified toxicity probability interval design. The primary objectives were safety, tolerability, and ORR by investigator assessment per RECIST v1.1 of the maximum administered or tolerated dose (MAD/MTD) of pembrolizumab+trametinib. Safety was analyzed for all patients who received ≥1 dose of study drug; patients treated during the trametinib run-in who discontinued study before receiving pembrolizumab were included; patients who did not complete trametinib run-in or receive ≥66% of planned doses during the 6-week dose-limiting toxicity (DLT) evaluable period were not included for DLT evaluation. AEs were graded per NCI CTCAE v4. Results Of 42 enrolled patients, most were female (61.9%); median age was 55.0 years; 57.1% had received ≥2 prior lines of therapy. At database cutoff (June 26, 2019), median follow-up was 9.0 months (range, 1.4-25.6 months). Of 38 DLT-evaluable patients, 10 had DLTs (table 1). Dosing regimens were selected for confirmation in part 5 based on safety data. Any-grade TRAEs occurred in 39 (92.9%) patients; grade 3-4 TRAEs occurred in 19 (45.2%), none were grade 5. TRAEs led to discontinuation in 8 (19.0%) patients. Immune-mediated AEs occurred in 12 (28.6%) patients, most commonly severe skin reactions (n=6; 14.3%), pneumonitis (n=3; 7.1%), hypothyroidism (n=2; 4.8%). The MTD of concurrent pembrolizumab+trametinib was pembrolizumab 200 mg Q3W plus trametinib 1.5 mg with 2 weeks of trametinib run-in (ORR, 0/16; 0%) and the MTD of intermittent pembrolizumab+trametinib was pembrolizumab 200 mg Q3W plus trametinib 2 mg with 2 weeks of run-in (ORR, 4/15; 26.7%). Conclusions Both concurrent or intermittent pembrolizumab+trametinib dosing were feasible and the combination showed antitumor activity in patients with advanced solid tumors or advanced BRAF wild-type melanoma.
- Published
- 2020
24. Adjuvant dabrafenib plus trametinib versus placebo in patients with resected, BRAFV600-mutant, stage III melanoma (COMBI-AD): exploratory biomarker analyses from a randomised, phase 3 trial
- Author
-
Matthew Squires, Victoria Atkinson, Eduard Gasal, James Larkin, Richard F. Kefford, James Garrett, Axel Hauschild, Daniel Gusenleitner, Vanna Chiarion-Sileni, Caroline Robert, John M. Kirkwood, Jan C. Brase, Catarina D. Campbell, Mario Mandalà, Dirk Schadendorf, Reinhard Dummer, Mario Santinami, Georgina V. Long, Keith T. Flaherty, University of Zurich, and Dummer, Reinhard
- Subjects
0301 basic medicine ,Oncology ,medicine.medical_specialty ,Salvage therapy ,610 Medicine & health ,Placebo ,law.invention ,03 medical and health sciences ,0302 clinical medicine ,Randomized controlled trial ,law ,Internal medicine ,Medicine ,Survival rate ,Trametinib ,business.industry ,10177 Dermatology Clinic ,Dabrafenib ,Clinical trial ,030104 developmental biology ,030220 oncology & carcinogenesis ,Biomarker (medicine) ,2730 Oncology ,business ,medicine.drug - Abstract
Summary Background Adjuvant dabrafenib plus trametinib reduced the risk of relapse versus placebo in patients with resected, BRAFV600-mutant, stage III melanoma in the phase 3 COMBI-AD trial. This prespecified exploratory biomarker analysis aimed to evaluate potential prognostic or predictive factors and mechanisms of resistance to adjuvant targeted therapy. Methods COMBI-AD is a randomised, double-blind, placebo-controlled, phase 3 trial comparing dabrafenib 150 mg orally twice daily plus trametinib 2 mg orally once daily versus two matched placebos. Study participants were at least 18 years of age and underwent complete resection of stage IIIA (lymph node metastases >1 mm), IIIB, or IIIC cutaneous melanoma, per American Joint Committee on Cancer 7th edition criteria, with a BRAFV600E or BRAFV600K mutation. Patients were randomly assigned (1:1) to the two treatment groups by an interactive voice response system, stratified by mutation type and disease stage. Patients, physicians, and the investigators who analysed data were masked to treatment allocation. The primary outcome was relapse-free survival, defined as the time from randomisation to disease recurrence or death from any cause. Biomarker assessment was a prespecified exploratory outcome of the trial. We assessed intrinsic tumour genomic features by use of next-generation DNA sequencing and characteristics of the tumour microenvironment by use of a NanoString RNA assay, which might provide prognostic and predictive information. This trial is registered with ClinicalTrials.gov , number NCT01682083 , and is ongoing but no longer recruiting participants. Findings Between Jan 31, 2013, and Dec 11, 2014, 870 patients were enrolled in the trial. Median follow-up at data cutoff (April 30, 2018) was 44 months (IQR 38–49) in the dabrafenib plus trametinib group and 42 months (21–49) in the placebo group. Intrinsic tumour genomic features were assessed in 368 patients (DNA sequencing set) and tumour microenvironment characteristics were assessed in 507 patients (NanoString biomarker set). MAPK pathway genomic alterations at baseline did not affect treatment benefit or clinical outcome. An IFNγ gene expression signature higher than the median was prognostic for prolonged relapse-free survival in both treatment groups. Tumour mutational burden was independently prognostic for relapse-free survival in the placebo group (high TMB, top third; hazard ratio [HR] 0·56, 95% CI 0·37–0·85, p=0·0056), but not in the dabrafenib plus trametinib group (0·83, 95% CI 0·53–1·32, p=0·44). Patients with tumour mutational burden in the lower two terciles seem to derive a substantial long-term relapse-free survival benefit from targeted therapy (HR [versus placebo] 0·49, 95% CI 0·35–0·68, p Interpretation Tumour mutational burden alone or in combination with IFNγ gene expression signature or other markers for an adaptive immune response might be of relevance for identifying patients with stage III melanoma who might derive clinical benefit from targeted therapy. Further validation in prospective clinical trials is warranted. Funding Novartis Pharmaceuticals.
- Published
- 2020
25. Long-term benefit of adjuvant dabrafenib + trametinib (D+T) in patients (pts) with resected stage III BRAF V600–mutant melanoma : Five-year analysis of COMBI-AD
- Author
-
Dirk Schadendorf, Caroline Dutriaux, Caroline Robert, Reinhard Dummer, John M. Kirkwood, Marta Nyakas, Mario Mandalà, Laurent Mortier, Axel Hauschild, Kohinoor Dasgupta, Monique Tan, Eduard Gasal, James Larkin, Jacob Schachter, Vanna Chiarion Sileni, Andrew Haydon, Victoria Atkinson, Mario Santinami, and Georgina V. Long
- Subjects
Oncology ,Trametinib ,Cancer Research ,medicine.medical_specialty ,business.industry ,medicine.medical_treatment ,Melanoma ,Mutant ,Medizin ,Dabrafenib ,Placebo ,medicine.disease ,03 medical and health sciences ,0302 clinical medicine ,030220 oncology & carcinogenesis ,Internal medicine ,medicine ,In patient ,Stage (cooking) ,business ,Adjuvant ,030215 immunology ,medicine.drug - Abstract
10001 Background: Previous results of the COMBI-AD trial (NCT01682083) showed a significant relapse-free survival (RFS) benefit with 12 mo of adjuvant D+T vs placebo (PBO) in pts with high-risk resected stage III BRAF V600E/K–mutant melanoma. In the primary analysis, 3-year RFS rates with D+T vs PBO were 58% vs 39% (hazard ratio [HR], 0.47 [95% CI, 0.39-0.58]; P < .001). An interim analysis of overall survival (OS) yielded 3-year OS rates of 86% with D+T vs 77% with PBO (HR, 0.57 [95% CI, 0.42-0.79]). Here we report data from 5-year analyses including long-term RFS and an updated cure rate model. Methods: COMBI-AD is a randomized, Phase III trial evaluating 12 mo of adjuvant D 150 mg twice daily + T 2 mg once daily vs 2 matched PBOs in pts with resected stage III BRAF V600E/K–mutant melanoma. Pts were stratified by BRAF status and disease stage (per AJCC 7 criteria). The primary endpoint is RFS; secondary endpoints include OS and distant metastasis–free survival (DMFS). A Weibull mixture cure rate model was applied to estimate the fraction of pts who will remain relapse free in the long term. As all patients had completed treatment by the time of the primary analysis, updated safety analyses were not performed. Results: This analysis represents a median follow-up of 60 mo for the D+T arm and 59 mo for the PBO arm. As of the data cutoff (Nov 8, 2019), 190 of 438 pts in the D+T arm and 262 of 432 pts in the PBO arm had an RFS event. Median RFS was not reached (NR; 95% CI, 47.9 mo-NR) with D+T vs 16.6 mo (95% CI, 12.7-22.1 mo) with PBO (HR, 0.51 [95% CI, 0.42-0.61]). The 4- and 5-year RFS rates were 55% (95% CI, 50%-60%) and 52% (95% CI, 48%-58%) with D+T vs 38% (95% CI, 34%-43%) and 36% (95% CI, 32%-41%) with PBO. These findings match those estimated by the cure rate model. The RFS benefit with D+T was evident across all AJCC 7 substages (HR [95% CI]: IIIA, 0.61 [0.35-1.07]; IIIB, 0.50 [0.37-0.67]; IIIC, 0.48 [0.36-0.64]). Median DMFS was NR in either arm but favored D+T (HR, 0.55 [95% CI, 0.44-0.70]). OS was not updated at this data cutoff as the prespecified number of events for the final OS analysis had not yet occurred. Conclusions: This 5-year analysis confirms the long-term benefit of adjuvant D+T in pts with resected stage III BRAF V600E/K–mutant melanoma. Clinical trial information: NCT01682083.
- Published
- 2020
26. The anti–PD-1 antibody spartalizumab in combination with dabrafenib and trametinib in advanced BRAF V600–mutant melanoma : Efficacy and safety findings from parts 1 and 2 of the Phase III COMBI-i trial
- Author
-
Aisha Masood, Keith T. Flaherty, Reinhard Dummer, Erika Richtig, Hussein Abdul-Hassan Tawbi, Céleste Lebbé, Neha Pakhle, Caroline Robert, Paul Nathan, Naoya Yamazaki, Mario Mandalà, Dirk Schadendorf, Victoria Atkinson, Paolo A. Ascierto, Ana Arance, Antoni Ribas, Georgina V. Long, and Eduard Gasal
- Subjects
Trametinib ,Cancer Research ,business.industry ,Melanoma ,medicine.medical_treatment ,Anti pd 1 ,Mutant ,Medizin ,Dabrafenib ,medicine.disease ,Targeted therapy ,03 medical and health sciences ,0302 clinical medicine ,Oncology ,030220 oncology & carcinogenesis ,Cancer research ,Medicine ,In patient ,business ,030215 immunology ,medicine.drug ,Advanced melanoma - Abstract
10028 Background: Treatment (tx) with checkpoint inhibitors or targeted therapy improves outcomes in patients (pts) with BRAF V600–mutant advanced melanoma; however, many pts subsequently progress and die. Preliminary evidence suggests that targeted therapy may enhance the impact of checkpoint inhibitors and improve efficacy compared with either treatment alone. Methods: COMBI-i is investigating first-line spartalizumab 400 mg every 4 wk + dabrafenib 150 mg twice daily + trametinib 2 mg once daily in pts with unresectable or metastatic BRAF V600–mutant melanoma (NCT02967692). We report efficacy and safety data from parts 1 (run-in cohort) and 2 (biomarker cohort), with a median follow-up of 24.3 mo. Response was assessed per RECIST v1.1. The randomized part 3 is ongoing. Results: 36 pts were enrolled (part 1: n = 9; part 2: n = 27); 20 (56%) had stage IV M1c disease and 15 (42%) had elevated lactate dehydrogenase (LDH) levels (≥ upper limit of normal). At the data cutoff (August 19, 2019), tx was ongoing in 10 pts (28%). The confirmed investigator-assessed objective response rate (ORR) was 78% (n = 28), with 16 complete responses (CRs; 44%) and 12 partial responses (33%). Median duration of response (DOR; 10/28 responders with events) was not reached (NR); 24-mo DOR rate was 53.4% (95% CI, 29%-73%). Median progression-free survival (PFS) was 22.7 mo; 24-mo PFS rate was 41.4% (95% CI, 23%-59%). At the cutoff, median overall survival (OS) was NR, with a 24-mo OS rate of 74.1% (95% CI, 56%-86%). In pts with elevated LDH, ORR was 67%, with 4 CRs (27%); median PFS was 10.7 mo (95% CI, 4.6-19.1 mo), and median OS was NR. The estimated 24-mo PFS and OS rates in these pts were 26.7% and 52.5%, respectively. All pts had ≥ 1 tx-related adverse event (TRAEs); 26 (72%) had grade ≥ 3 TRAEs. The most common grade ≥ 3 TRAEs were pyrexia (17%), increased lipase (11%), neutropenia (11%), increased blood creatine phosphokinase (8%), and increased γ-glutamyltransferase (8%). AEs leading to discontinuation of all 3 study drugs occurred in 6 pts (17%). All-causality grade ≥ 3 AEs requiring immunosuppressive medication occurred in 19 pts (53%). One pt died of cardiac arrest that was not considered tx related. Conclusions: The combination of spartalizumab + dabrafenib + trametinib resulted in high ORR and CR rates, with a high frequency of durable responses, including in patients with poor prognostic factors. Clinical trial information: NCT02967692.
- Published
- 2020
27. Five-Year Analysis of Adjuvant Dabrafenib plus Trametinib in Stage III Melanoma
- Author
-
Caroline Robert, Jacob Schachter, Thierry Lesimple, C. Dutriaux, Dirk Schadendorf, Monique Tan, Axel Hauschild, Georgina V. Long, R. Dummer, Eduard Gasal, Mario Santinami, Kohinoor Dasgupta, James Larkin, Mario Mandalà, Andrew M. Haydon, John M. Kirkwood, Vanna Chiarion Sileni, Laurent Mortier, Victoria Atkinson, Marta Nyakas, Ruth Plummer, and University of Zurich
- Subjects
Male ,Oncology ,Skin Neoplasms ,medicine.medical_treatment ,Medizin ,Administration, Oral ,2700 General Medicine ,030204 cardiovascular system & hematology ,law.invention ,0302 clinical medicine ,Randomized controlled trial ,law ,Antineoplastic Combined Chemotherapy Protocols ,Oximes ,Medicine ,030212 general & internal medicine ,Neoplasm Metastasis ,Melanoma ,Trametinib ,Imidazoles ,Follow up studies ,10177 Dermatology Clinic ,General Medicine ,Middle Aged ,Female ,Adjuvant ,medicine.drug ,Adult ,Proto-Oncogene Proteins B-raf ,medicine.medical_specialty ,Pyridones ,610 Medicine & health ,Pyrimidinones ,Disease-Free Survival ,03 medical and health sciences ,Adjuvants, Immunologic ,Double-Blind Method ,Internal medicine ,Humans ,Stage III melanoma ,Protein Kinase Inhibitors ,Survival analysis ,Aged ,Neoplasm Staging ,business.industry ,Dabrafenib ,Survival Analysis ,Clinical trial ,Mutation ,business ,Follow-Up Studies - Abstract
BACKGROUND In the previously reported primary analysis of this phase 3 trial, 12 months of adjuvant dabrafenib plus trametinib resulted in significantly longer relapse-free survival than placebo in patients with resected stage III melanoma with BRAF V600E or V600K mutations. To confirm the stability of the relapse-free survival benefit, longer-term data were needed. METHODS We randomly assigned 870 patients who had resected stage III melanoma with BRAF V600E or V600K mutations to receive 12 months of oral dabrafenib (at a dose of 150 mg twice daily) plus trametinib (2 mg once daily) or two matched placebos. The primary end point was relapse-free survival. Here, we report 5-year results for relapse-free survival and survival without distant metastasis as the site of the first relapse. Overall survival was not analyzed, since the required number of events to trigger the final overall survival analysis had not been reached. RESULTS The minimum duration of follow-up was 59 months (median patient follow-up, 60 months for dabrafenib plus trametinib and 58 months for placebo). At 5 years, the percentage of patients who were alive without relapse was 52% (95% confidence interval [CI], 48 to 58) with dabrafenib plus trametinib and 36% (95% CI, 32 to 41) with placebo (hazard ratio for relapse or death, 0.51; 95% CI, 0.42 to 0.61). The percentage of patients who were alive without distant metastasis was 65% (95% CI, 61 to 71) with dabrafenib plus trametinib and 54% (95% CI, 49 to 60) with placebo (hazard ratio for distant metastasis or death, 0.55; 95% CI, 0.44 to 0.70). No clinically meaningful between-group difference in the incidence or severity of serious adverse events was reported during the follow-up period. CONCLUSIONS In the 5-year follow-up of a phase 3 trial involving patients who had resected stage III melanoma with BRAF V600E or V600K mutations, 12 months of adjuvant therapy with dabrafenib plus trametinib resulted in a longer duration of survival without relapse or distant metastasis than placebo with no apparent long-term toxic effects. (Funded by GlaxoSmithKline and Novartis; COMBI-AD ClinicalTrials.gov number, NCT01682083; EudraCT number, 2012-001266-15.).
- Published
- 2020
28. Effect of first-line spartalizumab + dabrafenib + trametinib on immunosuppressive features detected in peripheral blood and clinical outcome in patients (pts) with advanced BRAF V600–mutant melanoma
- Author
-
Hussein Abdul-Hassan Tawbi, Victoria Atkinson, Paul Nathan, Naoya Yamazaki, Radha Ramesh, Daniel Gusenleitner, Paolo A. Ascierto, Céleste Lebbé, Eduard Gasal, Dirk Schadendorf, Reinhard Dummer, Caroline Robert, Jan C. Brase, Keith T. Flaherty, Georgina V. Long, Mario Mandalà, Antoni Ribas, Kelly Biette, Erika Richtig, and Ana Arance
- Subjects
Trametinib ,Oncology ,Cancer Research ,medicine.medical_specialty ,business.industry ,First line ,Melanoma ,Mutant ,Medizin ,Dabrafenib ,medicine.disease ,Peripheral blood ,03 medical and health sciences ,0302 clinical medicine ,030220 oncology & carcinogenesis ,Internal medicine ,medicine ,In patient ,business ,Complete response ,030215 immunology ,medicine.drug - Abstract
10034 Background: Spartalizumab + dabrafenib + trametinib has previously shown a high response rate of 78% (28 of 36 pts), with a complete response (CR) rate of 42%. A correlative analysis of gene expression signatures (GES)/pathways using whole-transcriptome RNA-seq data from tissue showed that pts with a CR had significantly lower expression levels of immunosuppressive factors in the tumor microenvironment (TME) at baseline (BL). Here we analyze BL peripheral blood markers in the same cohort of pts to assess whether liquid markers can also predict response and clinical outcome to spartalizumab + dabrafenib + trametinib. Methods: The Phase III COMBI-i study (NCT02967692) is evaluating spartalizumab + dabrafenib + trametinib in pts with previously untreated BRAF V600–mutant unresectable or metastatic melanoma. In parts 1 (safety run-in; n = 9) and 2 (biomarker cohort; n = 27), blood and tissue samples were collected at BL, on treatment after 2-3 wk and 8-12 wk, and at disease progression. Lactate dehydrogenase (LDH) and other blood-based markers (including cytokine profiling [n = 45] and blood RNA-seq [114 signatures]) were assessed in all 36 pts. Pts were divided into 2 groups of 24 and 12 pts based on progression-free survival (PFS) of > 1 or < 1 y. Results: In addition to LDH, previously described blood markers such as neutrophil to lymphocyte ratio (NLR) and plasma IL-8 were identified among other neutrophil and immunosuppressive features as top candidates associated with PFS > 1 y. Low plasma IL-8 levels were also associated with CR, and multivariate models suggested that IL-8 may add independent predictive value to LDH and NLR for PFS > 1 y and CR. Pts with high IL-8 levels in the circulation were characterized by high neutrophil chemokine signaling (ρ = 0.553) and high neutrophil markers (ρ = 0.466) in the tumor as measured by RNA-seq GES levels. We observed a decrease in plasma IL-8 levels from BL upon treatment with spartalizumab + dabrafenib + trametinib. Conclusions: Our peripheral blood marker analysis confirmed recent findings from tissue samples that intratumoral immunosuppressive features may preclude a CR and are associated with poor outcomes. High BL plasma IL-8 levels may be associated with an immunosuppressive TME. Further validation is warranted; the randomized placebo-controlled part 3 of COMBI-i is ongoing. Clinical trial information: NCT02967692.
- Published
- 2020
29. Combined PD-1, BRAF and MEK inhibition in advanced BRAF-mutant melanoma : safety run-in and biomarker cohorts of COMBI-i
- Author
-
Eduard Gasal, Paul Nathan, Antoni Ribas, Neha Pakhle, Victoria Atkinson, Céleste Lebbé, Dirk Schadendorf, Mario Mandalà, Daniel Gusenleitner, Paolo A. Ascierto, Aisha Masood, Erika Richtig, Catarina D. Campbell, Reinhard Dummer, Ana Arance, Keith T. Flaherty, Hussein Abdul-Hassan Tawbi, Naoya Yamazaki, Georgina V. Long, Caroline Robert, Jan C. Brase, University of Zurich, and Dummer, Reinhard
- Subjects
0301 basic medicine ,Oncology ,Male ,Skin Neoplasms ,Medizin ,Cohort Studies ,0302 clinical medicine ,Antineoplastic Agents, Immunological ,Antineoplastic Combined Chemotherapy Protocols ,Oximes ,Clinical endpoint ,Neoplasm Metastasis ,Immune Checkpoint Inhibitors ,Melanoma ,Trametinib ,MEK inhibitor ,Imidazoles ,10177 Dermatology Clinic ,General Medicine ,Middle Aged ,MAP Kinase Kinase Kinases ,Treatment Outcome ,030220 oncology & carcinogenesis ,Disease Progression ,Biomarker (medicine) ,Female ,medicine.drug ,Adult ,Proto-Oncogene Proteins B-raf ,medicine.medical_specialty ,Pyridones ,Mutation, Missense ,610 Medicine & health ,Genetics and Molecular Biology ,Pyrimidinones ,Antibodies, Monoclonal, Humanized ,General Biochemistry, Genetics and Molecular Biology ,03 medical and health sciences ,Young Adult ,1300 General Biochemistry, Genetics and Molecular Biology ,Internal medicine ,medicine ,Biomarkers, Tumor ,Humans ,Protein Kinase Inhibitors ,Aged ,business.industry ,Dabrafenib ,medicine.disease ,Clinical trial ,Regimen ,030104 developmental biology ,General Biochemistry ,business - Abstract
Immune and targeted therapies achieve long-term survival in metastatic melanoma; however, new treatment strategies are needed to improve patients’ outcomes1,2. We report on the efficacy, safety and biomarker analysis from the single-arm safety run-in (part 1; n = 9) and biomarker (part 2; n = 27) cohorts of the randomized, placebo-controlled, phase 3 COMBI-i trial (NCT02967692) of the anti-PD-1 antibody spartalizumab, in combination with the BRAF inhibitor dabrafenib and MEK inhibitor trametinib. Patients (n = 36) had previously untreated BRAF V600-mutant unresectable or metastatic melanoma. In part 1, the recommended phase 3 regimen was identified based on the incidence of dose-limiting toxicities (DLTs; primary endpoint): 400 mg of spartalizumab every 4 weeks plus 150 mg of dabrafenib twice daily plus 2 mg of trametinib once daily. Part 2 characterized changes in PD-L1 levels and CD8+ cells following treatment (primary endpoint), and analyzed additional biomarkers. Assessments of efficacy and safety were key secondary endpoints (median follow-up, 24.3 months). Spartalizumab plus dabrafenib and trametinib led to an objective response rate (ORR) of 78%, including 44% complete responses (CRs). Grade ≥3 treatment-related adverse events (TRAEs) were experienced by 72% of patients. All patients had temporary dose modifications, and 17% permanently discontinued all three study drugs due to TRAEs. Early progression-free survival (PFS) events were associated with low tumor mutational burden/T cell–inflamed gene expression signature (GES) or high immunosuppressive tumor microenvironment (TME) GES levels at baseline; an immunosuppressive TME may also preclude CR. Overall, the efficacy, safety and on-treatment biomarker modulations associated with spartalizumab plus dabrafenib and trametinib are promising, and biomarkers that may predict long-term benefit were identified. Clinical activity and biomarker analysis from the COMBI-i trial evaluating PD-1, BRAF and MEK inhibition in patients with metastatic melanoma demonstrate high response rates and uncover molecular correlates of long-term treatment benefit.
- Published
- 2020
30. Abstract CT025: Dabrafenib plus trametinib in BRAF V600E-mutant high-grade (HGG) and low-grade glioma (LGG)
- Author
-
Nikolas von Bubnoff, Martin J. van den Bent, Antje Wick, Jean-Yves Blay, Myra E. van Linde, Alexander Stein, Gerald W. Prager, Filip de Vos, Mario Campone, Eduard Gasal, Ralf-Dieter Hofheinz, Anas Gazzah, Angelica Fasolo, Jose A. Lopez-Martin, Jeffrey Yachnin, Patrick Y. Wen, Vivek Subbiah, Palanichamy Ilankumaran, Tae Min Kim, Aislyn Boran, Albert Lai, Damien Pouessel, Paul Burgess, and Daniel C. Cho
- Subjects
Trametinib ,Cancer Research ,medicine.medical_specialty ,business.industry ,MEK inhibitor ,Melanoma ,Dabrafenib ,Neutropenia ,medicine.disease ,Gastroenterology ,Oncology ,Diffuse Astrocytoma ,Glioma ,Internal medicine ,medicine ,business ,medicine.drug ,Anaplastic astrocytoma - Abstract
Background: More effective treatments are needed to improve outcomes in HGG and LGG. Activating BRAF mutations occur in ~3% of glioblastomas and 15% of LGGs. BRAF inhibitor dabrafenib + MEK inhibitor trametinib combination is FDA-approved in BRAF V600-positive melanoma, NSCLC, and anaplastic thyroid cancer. Methods: We conducted a nonrandomized, open-label, phase 2 basket study (NCT02034110) of dabrafenib + trametinib in pts with BRAF V600E mutation-positive rare cancers; here we report results for the HGG and LGG cohorts. Adult pts with histologically confirmed recurrent/progressive HGG (Grade III, IV) or LGG (Grade I, II) per WHO 2007 classification received oral dabrafenib, 150 mg twice daily, and oral trametinib, 2 mg once daily, until unacceptable toxicity, disease progression, or death. The primary endpoint was investigator-assessed objective response rate (ORR) using RANO criteria. Secondary endpoints included progression-free survival (PFS), duration of response (DOR), overall survival (OS), and safety; molecular characterization of baseline tumor samples was an exploratory endpoint. Results: As of Sept 14, 2020, 45 pts (23 male) were enrolled in the HGG cohort; 35 discontinued, 6 remained on treatment, 4 were in follow up. The majority had glioblastoma (69%), followed by anaplastic pleomorphic xanthoastrocytoma and anaplastic astrocytoma (each 11%); of pts with known IDH/MGMT status, 3/29 pts had IDH1 mutations and 8/17 had MGMT promoter methylation. Prior therapies included radiotherapy (98%), surgery, and chemotherapy (93% each). Median (range) follow-up was 12.7 (1.1-56.1) months (mo); ORR was 33% (3 CR, 12 PR); median DOR was 36.9 mo (95% CI, 7.4-44.2). Median PFS and OS were 3.8 mo (95% CI, 1.8-9.2) and 17.6 mo (95% CI, 9.5-45.2), respectively. The LGG cohort enrolled 13 pts (4 male); 7 discontinued, 5 remained on treatment, 1 was in follow up. Most common histologies were ganglioglioma (31%), diffuse astrocytoma, and pleomorphic xanthoastrocytoma (each 15%); of pts with known IDH/MGMT status, 1/8 pts had IDH1 mutation and 0/2 had MGMT promoter methylation. Prior therapies included surgery (92%), radiotherapy (62%), and chemotherapy (38%). Median (range) follow-up was 32.2 (0.8-71.8) mo; ORR was 69% (1 CR, 6 PR, 2 MR); median DOR, PFS, and OS were not reached. Overall, 54/58 pts (93%) experienced adverse events (AEs) across cohorts, most commonly (≥30%) fatigue (50%), headache (43%), nausea (34%), and pyrexia (33%); 31 pts (53%) had grade ≥3 AEs, most commonly (≥5%) fatigue, decreased neutrophil count (9% each), headache, and neutropenia (5% each). Next-generation sequencing showed a heterogenous landscape and low tumor mutation burden. Conclusions: Dabrafenib + trametinib demonstrated promising efficacy in pts with BRAF V600E mutation-positive recurrent/refractory HGG and LGG. The safety profile was consistent with the known safety profile for other indications. Citation Format: Vivek Subbiah, Alexander Stein, Martin van den Bent, Antje Wick, Filip Y. de Vos, Nikolas von Bubnoff, Myra E. van Linde, Albert Lai, Gerald W. Prager, Mario Campone, Angelica Fasolo, Jose A. Lopez-Martin, Tae Min Kim, Ralf-Dieter Hofheinz, Jean-Yves Blay, Daniel C. Cho, Anas Gazzah, Damien Pouessel, Jeffrey Yachnin, Aislyn Boran, Paul Burgess, Palanichamy Ilankumaran, Eduard Gasal, Patrick Y. Wen. Dabrafenib plus trametinib in BRAF V600E-mutant high-grade (HGG) and low-grade glioma (LGG) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr CT025.
- Published
- 2021
31. Oncolytic immunotherapy: unlocking the potential of viruses to help target cancer
- Author
-
Richard D. Carvajal, Brianna Hoffner, Omid Hamid, Eduard Gasal, and Jenny Jimmy Hong
- Subjects
0301 basic medicine ,Cancer Research ,viruses ,medicine.medical_treatment ,Immunology ,Review ,Virus ,03 medical and health sciences ,0302 clinical medicine ,Cancer immunotherapy ,Oncolytic immunotherapy ,medicine ,Humans ,Immunology and Allergy ,Virotherapy ,Talimogene laherparepvec ,Melanoma ,Oncolytic Virotherapy ,business.industry ,Cancer ,Immunotherapy ,medicine.disease ,Oncolytic virus ,Oncolytic Viruses ,030104 developmental biology ,Oncology ,030220 oncology & carcinogenesis ,Cancer research ,business - Abstract
Oncolytic immunotherapy is a research area of cancer immunotherapy investigating the use of modified viruses to target cancer cells. A variety of different viral backbones (e.g., adenovirus, reovirus) with a diverse range of genetic modifications are currently being investigated for the treatment of a variety of cancers. The oncolytic virus that has advanced the furthest in clinical development is talimogene laherparepvec, a recombinant HSV-1 virus expressing granulocyte-macrophage colony-stimulating factor (GM-CSF). In a phase 3 study in patients with unresectable metastatic melanoma, intralesional talimogene laherparepvec treatment resulted in a higher durable response rate compared with subcutaneous GM-CSF treatment (16.3 versus 2.1%; P
- Published
- 2017
32. ACTR-30. UPDATED EFFICACY AND SAFETY OF DABRAFENIB PLUS TRAMETINIB IN PATIENTS WITH RECURRENT/REFRACTORY BRAF V600E–MUTATED HIGH-GRADE GLIOMA (HGG) AND LOW-GRADE GLIOMA (LGG)
- Author
-
Jean-Yves Blay, Tae Min Kim, Paul Burgess, Patrick Y. Wen, Vivek Subbiah, Mario Campone, Gerald W. Prager, Ralf-Dieter Hofheinz, Albert Lai, Martin J. van den Bent, Angelica Fasolo, Ilan Palanichamy, Sascha Dietrich, Nikolas von Bubnoff, Jeffrey Yachnin, Filip de Vos, Carlos Gomez-Roca, Warren P. Mason, Daniel Cho, Jacques De Greve, Alexander Stein, Eduard Gasal, Anas Gazzah, Jose A. Lopez-Martin, Aislyn Boran, and Myra van Linde
- Subjects
Oncology ,Trametinib ,Cancer Research ,medicine.medical_specialty ,business.industry ,Melanoma ,Dabrafenib ,Neutropenia ,medicine.disease ,Chemotherapy regimen ,Refractory ,Adult Clinical Trials - Non-Immunologic ,Glioma ,Internal medicine ,medicine ,Neurology (clinical) ,Progression-free survival ,business ,medicine.drug - Abstract
BACKGROUND There is a lack of treatment options for HGG and LGG patients. BRAFV600E mutations are uncommon in glioma, with a poor long-term prognosis. Combined BRAF/MEK inhibition extends progression-free survival (PFS) and overall survival (OS) in BRAF V600E–mutated melanoma, non small-cell lung cancer, and anaplastic thyroid cancer. METHODS This phase 2, open-label trial (NCT02034110) evaluated dabrafenib (BRAF inhibitor, 150mg BID) plus trametinib (MEK inhibitor, 2mg QD) in patients with BRAF V600E mutations in 9 rare tumor types, including HGG and LGG. Eligible patients had histologically-confirmed recurrent or progressive glioma (LGG:WHO grade 1 or 2; HGG:WHO grade 3 or 4), with HGG patients required to have received radiotherapy and first-line chemotherapy, or concurrent chemoradiation. Treatment continued until unacceptable toxicity, disease progression, or death. Primary endpoint was investigator-assessed objective response rate (ORR) using RANO criteria. Secondary endpoints included duration of response (DOR), PFS, OS, and safety. RESULTS Interim analysis (IA) #14 (data cutoff: April 2, 2018) reported additional 3 months follow-up, with 49 patients enrolled (HGG, n=39; LGG, n=10) and 3 patients not evaluable for response. In HGG patients, ORR was 27% (10/37; 95%CI: 13.8%-44.1%), including CR (n=1), PR (n=9), and SD (n=11), with 16 patients currently ongoing treatment. In LGG patients, ORR was 56% (5/9; 95%CI: 26.8%-79.3%), including PR (n=5) and SD (n=4), with 6 patients currently ongoing treatment. OS, PFS, and DOR will be presented (IA#15). In HGG patients, adverse events (AEs) included fatigue (33%), headache (31%), rash (28%), and pyrexia (23%); grade 3/4 AEs included neutropenia (8%) and fatigue (5%). In LGG patients, AEs included headache (70%), fatigue, pyrexia (60% each), nausea, and arthralgia (50% each); grade 3/4 AEs included fatigue (20%). CONCLUSIONS Dabrafenib plus trametinib demonstrated promising efficacy in patients with recurrent or refractory BRAF V600E‒mutated HGG or LGG, with manageable AEs and no new safety signals.
- Published
- 2019
33. Adverse event (AE) kinetics in patients (pts) treated with dabrafenib + trametinib (D + T) in the metastatic and adjuvant setting
- Author
-
Georgina V. Long, John M. Kirkwood, Eduard Gasal, M.A. Davies, J.-J. Grob, Paul Nathan, Dirk Schadendorf, Richard F. Kefford, Antoni Ribas, Paul Burgess, Victoria Atkinson, Reinhard Dummer, Caroline Robert, Axel Hauschild, and Keith T. Flaherty
- Subjects
Oncology ,Trametinib ,medicine.medical_specialty ,business.industry ,medicine.medical_treatment ,Melanoma ,Disease progression ,Dabrafenib ,Hematology ,medicine.disease ,Internal medicine ,medicine ,In patient ,Adverse effect ,Vemurafenib ,business ,Adjuvant ,medicine.drug - Published
- 2019
34. Analysis of pyrexia in patients (pts) treated with dabrafenib (D) and/or trametinib (T) across clinical trials
- Author
-
E. de Jong, Anthony D'Amelio, Eduard Gasal, Keith T. Flaherty, Dirk Schadendorf, H.A. Tawbi, Reinhard Dummer, Georgina V. Long, C. Robert, and A.M. Menzies
- Subjects
0301 basic medicine ,Metastatic melanoma ,business.industry ,Stock options ,Hematology ,Management ,Clinical trial ,03 medical and health sciences ,030104 developmental biology ,0302 clinical medicine ,Pooled analysis ,Oncology ,Shareholder ,030220 oncology & carcinogenesis ,Medicine ,Dose reduction ,Stage III melanoma ,In patient ,business - Abstract
Background D+T has been approved for several indications, including BRAF V600–mutant unresectable or metastatic melanoma and as adjuvant therapy following resected BRAF V600–mutant stage III melanoma. Pyrexia is a common adverse event but is generally low-grade and manageable; further characterization may optimize management and reduce permanent treatment (tx) discontinuation due to pyrexia. Methods Trial databases were queried for reports of pyrexia in pts treated with D and/or T, including adjuvant therapy. Indications included unresectable, metastatic, or resected stage III melanoma; non-small cell lung cancer (NSCLC); colorectal cancer, and other BRAF–mutation positive solid tumors. Data for D+T was compiled from the following trials: COMBI-AD (NCT01682083), COMBI-d (NCT01584648), COMBI-v (NCT01597908), and BRF113928 (NCT01336634). Pyrexia was graded according to the Common Terminology Criteria for Adverse Events version 4.0. Results A total of 1991 pts were included from clinical trials (D+T, n=1076; D, n=586; T, n=329). Pyrexia was observed in 904 pts: D+T, 61% (660/1076); D, 33% (196/586); T, 15% (48/329). Of pts treated with D+T, 6% (62/1076) experienced grade 3 events and 1 of 1076 pts experienced a grade 4 event. The median time to onset was 27 d (range, 1-716 d). Recurrent any-grade pyrexia occurred in 41% (442/1076) of pts; 29% had ≥ 3 episodes. Of the 442 pts with recurrent pyrexia, 377 (85%) experienced a subsequent event within 3mo of the first pyrexia episode. No pyrexia-related deaths were reported. Outcomes were reported for 2252 of 2253 events in pts treated with D+T across trials. Pyrexia management strategies included: tx interruption (939/2253 events [42%]), dose reduction (225/2253 [10%]), and tx discontinuation (62/2253 [3%]); ≥ 98% of events were reported to be resolved following each of the aforementioned interventions. Conclusions Pyrexia in pts treated with D+T is typically low-grade, occurs early during tx exposure, and most pts experience ≤ 1 episode. Tx interruption was the most frequent intervention strategy used in clinical trials. Pyrexia can be effectively managed with nearly all events reported to have been resolved at the time of the analysis. Clinical trial identification Pooled analysis of data from the following trials: NCT01227889, NCT01153763, NCT01266967, NCT01072175, NCT00880321, NCT01336634, NCT01584648, NCT01597908, NCT01682083, NCT01245062, NCT01037127, NCT00687622. Editorial acknowledgement Allison Lytle, PhD, from ArticulateScience LLC, funded by Novartis Pharmaceuticals Corporation. Legal entity responsible for the study Novartis Pharmaceuticals Corporation. Funding Novartis Pharmaceuticals Corporation. Disclosure C. Robert: Non-remunerated activity/ies, Medical writing assistance: ArticulateScience LLC; Advisory / Consultancy: Bristol-Myers Squibb; Advisory / Consultancy: Roche; Advisory / Consultancy: MSD; Advisory / Consultancy: Novartis; Advisory / Consultancy: Pierre Fabre; Advisory / Consultancy: Array; Advisory / Consultancy: Sanofi; Advisory / Consultancy: Merck. D. Schadendorf: Non-remunerated activity/ies, Medical writing assistance: ArticulateScience LLC; Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: Roche/Genentech; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony, Research grant / Funding (self), Travel / Accommodation / Expenses: Novartis; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony, Research grant / Funding (self), Travel / Accommodation / Expenses: Bristol-Myers Squibb; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony: Merck Sharp & Dohme; Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: Merck Serono; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony, Travel / Accommodation / Expenses: Amgen; Honoraria (self), Advisory / Consultancy: Immunocore; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony: Incyte; Honoraria (self), Advisory / Consultancy: 4SC; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony: Pierre Fabre; Honoraria (self), Advisory / Consultancy: Mologen; Advisory / Consultancy: Sanofi/Regeneron; Speaker Bureau / Expert testimony: Roche; Travel / Accommodation / Expenses: Merck; Honoraria (self): Sysmex; Honoraria (self): Grunenthal Group; Honoraria (self): Agenus; Honoraria (self): Array BioPharma; Honoraria (self): AstraZeneca; Honoraria (self): LEO Pharma; Honoraria (self): Pfizer; Honoraria (self): Philogen; Honoraria (self): Regeneron. R. Dummer: Non-remunerated activity/ies, Medical writing assistance: ArticulateScience LLC; Advisory / Consultancy, Intermittent, project focused consulting and/or advisory relationship: Novartis; Advisory / Consultancy, Intermittent, project focused consulting and/or advisory relationship: Merck Sharp & Dhome; Advisory / Consultancy, Intermittent, project focused consulting and/or advisory relationship: Bristol-Myers Squibb; Advisory / Consultancy, Intermittent, project focused consulting and/or advisory relationship: Roche; Advisory / Consultancy, Intermittent, project focused consulting and/or advisory relationship: Amgen; Advisory / Consultancy, Intermittent, project focused consulting and/or advisory relationship: Takeda; Advisory / Consultancy, Intermittent, project focused consulting and/or advisory relationship: Pierre Fabre; Advisory / Consultancy, Intermittent, project focused consulting and/or advisory relationship: Sun Pharma; Advisory / Consultancy, Intermittent, project focused consulting and/or advisory relationship: Sanofi; Advisory / Consultancy, Intermittent, project focused consulting and/or advisory relationship: Catalym. K.T. Flaherty: Non-remunerated activity/ies, Medical writing assistance: ArticulateScience LLC; Advisory / Consultancy, Research grant / Funding (institution): Novartis; Advisory / Consultancy: Genentech; Advisory / Consultancy: Merck; Advisory / Consultancy: Lilly; Advisory / Consultancy: Amgen; Advisory / Consultancy, Research grant / Funding (institution): Sanofi; Advisory / Consultancy, Shareholder / Stockholder / Stock options: Oncoceutics; Advisory / Consultancy: Bristol-Myers Squibb; Advisory / Consultancy: Adaptimmune; Advisory / Consultancy: Aeglea Biotherapeutics; Advisory / Consultancy, Shareholder / Stockholder / Stock options: Loxo; Advisory / Consultancy: Roche; Advisory / Consultancy: Asana Biosciences; Advisory / Consultancy: Incyte; Advisory / Consultancy, Shareholder / Stockholder / Stock options: Shattuck Labs; Advisory / Consultancy: Tolero Pharmaceuticals; Advisory / Consultancy: Array BioPharma; Advisory / Consultancy, Shareholder / Stockholder / Stock options: FOGPharma; Advisory / Consultancy: Neon Therapeutics; Advisory / Consultancy, Shareholder / Stockholder / Stock options: Tvardi; Advisory / Consultancy: Takeda; Advisory / Consultancy: Varestem; Advisory / Consultancy: Boston Biomedical; Advisory / Consultancy, Travel / Accommodation / Expenses: Pierre Fabre; Advisory / Consultancy: Cell Medica; Advisory / Consultancy, Travel / Accommodation / Expenses: Debiopharm Group; Shareholder / Stockholder / Stock options: Clovis Oncology; Shareholder / Stockholder / Stock options: X4 Pharma; Shareholder / Stockholder / Stock options: PIC Therapeutics; Shareholder / Stockholder / Stock options: Fount Therapeutics; Shareholder / Stockholder / Stock options: Apricity Health; Shareholder / Stockholder / Stock options: Vivid Biosciences; Shareholder / Stockholder / Stock options: Checkmate Pharmaceuticals; Shareholder / Stockholder / Stock options: Strata Oncology. H.A. Tawbi: Non-remunerated activity/ies, Medical writing assistance: ArticulateScience LLC; Advisory / Consultancy, Research grant / Funding (institution): Novartis; Advisory / Consultancy, Research grant / Funding (institution): Bristol-Myers Squibb; Advisory / Consultancy, Research grant / Funding (institution): Merck; Research grant / Funding (institution): GlaxoSmithKline; Advisory / Consultancy: Roche; Advisory / Consultancy: Array; Research grant / Funding (institution): Celgene. A.M. Menzies: Non-remunerated activity/ies, Medical writing assistance: ArticulateScience LLC; Advisory / Consultancy: Bristol-Myers Squibb; Advisory / Consultancy: MSD; Advisory / Consultancy: Novartis; Advisory / Consultancy: Roche; Advisory / Consultancy: Pierre Fabre. A. D'Amelio: Non-remunerated activity/ies, Medical writing assistance: ArticulateScience LLC; Shareholder / Stockholder / Stock options, Full / Part-time employment: Novartis; Shareholder / Stockholder / Stock options: GlaxoSmithKline. E. de Jong: Non-remunerated activity/ies, Medical writing assistance: ArticulateScience LLC; Shareholder / Stockholder / Stock options, Full / Part-time employment: Novartis. E. Gasal: Non-remunerated activity/ies, Medical writing assistance: ArticulateScience LLC; Shareholder / Stockholder / Stock options, Full / Part-time employment: Novartis. G.V. Long: Non-remunerated activity/ies, Medical writing assistance: ArticulateScience LLC; Honoraria (self), Advisory / Consultancy: Bristol-Myers Squibb; Advisory / Consultancy: Roche/Genentech; Advisory / Consultancy: Amgen; Honoraria (self), Advisory / Consultancy: Merck; Honoraria (self), Advisory / Consultancy: Novartis; Advisory / Consultancy: Array BioPharma; Advisory / Consultancy: Pierre Fabre.
- Published
- 2019
35. Adjuvant dabrafenib plus trametinib versus placebo in patients with resected, BRAF
- Author
-
Reinhard, Dummer, Jan C, Brase, James, Garrett, Catarina D, Campbell, Eduard, Gasal, Matthew, Squires, Daniel, Gusenleitner, Mario, Santinami, Victoria, Atkinson, Mario, Mandalà, Vanna, Chiarion-Sileni, Keith, Flaherty, James, Larkin, Caroline, Robert, Richard, Kefford, John M, Kirkwood, Axel, Hauschild, Dirk, Schadendorf, and Georgina V, Long
- Subjects
Adult ,Male ,Proto-Oncogene Proteins B-raf ,Skin Neoplasms ,Adolescent ,Pyridones ,Pyrimidinones ,Young Adult ,Double-Blind Method ,Antineoplastic Combined Chemotherapy Protocols ,Oximes ,Humans ,Neoplasm Metastasis ,Melanoma ,Aged ,Aged, 80 and over ,Salvage Therapy ,Imidazoles ,Middle Aged ,Prognosis ,Survival Rate ,Drug Resistance, Neoplasm ,Mutation ,Female ,Neoplasm Recurrence, Local ,Follow-Up Studies - Abstract
Adjuvant dabrafenib plus trametinib reduced the risk of relapse versus placebo in patients with resected, BRAFCOMBI-AD is a randomised, double-blind, placebo-controlled, phase 3 trial comparing dabrafenib 150 mg orally twice daily plus trametinib 2 mg orally once daily versus two matched placebos. Study participants were at least 18 years of age and underwent complete resection of stage IIIA (lymph node metastases1 mm), IIIB, or IIIC cutaneous melanoma, per American Joint Committee on Cancer 7th edition criteria, with a BRAFBetween Jan 31, 2013, and Dec 11, 2014, 870 patients were enrolled in the trial. Median follow-up at data cutoff (April 30, 2018) was 44 months (IQR 38-49) in the dabrafenib plus trametinib group and 42 months (21-49) in the placebo group. Intrinsic tumour genomic features were assessed in 368 patients (DNA sequencing set) and tumour microenvironment characteristics were assessed in 507 patients (NanoString biomarker set). MAPK pathway genomic alterations at baseline did not affect treatment benefit or clinical outcome. An IFNγ gene expression signature higher than the median was prognostic for prolonged relapse-free survival in both treatment groups. Tumour mutational burden was independently prognostic for relapse-free survival in the placebo group (high TMB, top third; hazard ratio [HR] 0·56, 95% CI 0·37-0·85, p=0·0056), but not in the dabrafenib plus trametinib group (0·83, 95% CI 0·53-1·32, p=0·44). Patients with tumour mutational burden in the lower two terciles seem to derive a substantial long-term relapse-free survival benefit from targeted therapy (HR [versus placebo] 0·49, 95% CI 0·35-0·68, p0·0001). However, patients with high tumour mutational burden seem to have a less pronounced benefit with targeted therapy (HR [versus placebo] 0·75, 95% CI 0·44-1·26, p=0·27), especially if they had an IFNγ signature lower than the median (HR 0·88 [95% CI 0·40-1·93], p=0·74).Tumour mutational burden alone or in combination with IFNγ gene expression signature or other markers for an adaptive immune response might be of relevance for identifying patients with stage III melanoma who might derive clinical benefit from targeted therapy. Further validation in prospective clinical trials is warranted.Novartis Pharmaceuticals.
- Published
- 2019
36. Efficacy and Safety of Dabrafenib in Pediatric Patients with
- Author
-
Darren R, Hargrave, Eric, Bouffet, Uri, Tabori, Alberto, Broniscer, Kenneth J, Cohen, Jordan R, Hansford, Birgit, Geoerger, Pooja, Hingorani, Ira J, Dunkel, Mark W, Russo, Lillian, Tseng, Kohinoor, Dasgupta, Eduard, Gasal, James A, Whitlock, and Mark W, Kieran
- Subjects
Male ,Proto-Oncogene Proteins B-raf ,Adolescent ,Maximum Tolerated Dose ,Brain Neoplasms ,Imidazoles ,Infant ,Glioma ,Progression-Free Survival ,Treatment Outcome ,Drug Resistance, Neoplasm ,Child, Preschool ,Oximes ,Humans ,Female ,Tissue Distribution ,Patient Safety ,Neoplasm Grading ,Neoplasm Recurrence, Local ,Child ,Protein Kinase Inhibitors - Abstract
Pediatric low-grade glioma (pLGG) is the most prevalent childhood brain tumor. Patients withPatients ages 1 to18 years who hadOverall, 32 patients with pLGG were enrolled (part 1,Dabrafenib demonstrated meaningful clinical activity and acceptable tolerability in patients with
- Published
- 2019
37. Reply to E. Hindié and K.R. Hess
- Author
-
Mark Shilkrut, Ruth Plummer, V. Chiarion-Sileni, Caroline Robert, Eduard Gasal, James Larkin, Axel Hauschild, Richard F. Kefford, Marta Nyakas, Victoria Atkinson, Kohinoor Dasgupta, Dirk Schadendorf, Caroline Dutriaux, Jacob Schachter, Reinhard Dummer, John M. Kirkwood, Mario Mandalà, Tomas Haas, Thierry Lesimple, Laurent Mortier, Georgina V. Long, Andrew Haydon, Mario Santinami, and University of Zurich
- Subjects
Oncology ,Cancer Research ,medicine.medical_specialty ,business.industry ,Melanoma ,MEDLINE ,Follow up studies ,Medizin ,10177 Dermatology Clinic ,610 Medicine & health ,medicine.disease ,Neoplasm Recurrence ,Pyrimidinones ,Text mining ,Internal medicine ,Dermatology clinic ,medicine ,2730 Oncology ,1306 Cancer Research ,business - Abstract
Korrespondenz zu 10.1200/JCO.18.01768 (Hess) und 10.1200/JCO.18.02075 (Hindié)
- Published
- 2019
38. Five-year analysis on the long-term effects of dabrafenib plus trametinib (D + T) in patients with BRAF V600–mutant unresectable or metastatic melanoma
- Author
-
Jean-Jacques Grob, Keith T. Flaherty, Claus Garbe, Antoni Ribas, Dirk Schadendorf, Igor Bondarenko, E. Levchenko, Axel Hauschild, Daniil Stroyakovskiy, Boguslawa Karaszewska, Eduard Gasal, Jacob Schachter, Paul Burgess, Vanna Chiarion Sileni, Monique Tan, Michael A. Davies, Paul Nathan, Georgina V. Long, and Caroline Robert
- Subjects
Trametinib ,Oncology ,Cancer Research ,medicine.medical_specialty ,Metastatic melanoma ,business.industry ,Mutant ,Medizin ,Dabrafenib ,03 medical and health sciences ,0302 clinical medicine ,030220 oncology & carcinogenesis ,Internal medicine ,Overall survival ,Medicine ,In patient ,business ,030215 immunology ,medicine.drug - Abstract
9507 Background: First-line treatment with D+T demonstrated prolonged progression-free survival (PFS) and overall survival (OS) in patients with BRAF V600–mutant unresectable or metastatic melanoma. With 5 years of follow-up, we report survival and describe characteristics of patients in the phase 3 COMBI-d and COMBI-v trials with long-term benefit. Methods: Pooled 5-year landmark data for patients treated with D+T in the phase 3 COMBI-d (NCT01584648) and COMBI-v (NCT01597908) trials were analyzed. The trials enrolled patients with previously untreated BRAF V600E/K–mutant unresectable or metastatic melanoma. Patients received D 150 mg twice daily plus T 2 mg once daily vs either D + placebo (COMBI-d) or vemurafenib (COMBI-v). The primary endpoints were PFS in COMBI-d and OS in COMBI-v. Results: The pooled population included 563 patients who received D+T (COMBI-d, n = 211; COMBI-v, n = 352). Four- and 5-year PFS and OS rates were similar, suggesting a stabilization (4- and 5-year PFS, 21% [95% CI, 17%-24%] and 19% [95% CI, 15%-22%, respectively]; 4- and 5-year OS, 37% [95% CI, 33%-42%] and 34% [95% CI, 30%-38%], respectively). In patients with normal baseline lactate dehydrogenase (LDH) levels the 5-year PFS rate was 25% vs 8% in patients with elevated baseline LDH levels. Similarly, the 5-year OS rate was considerably higher in patients with normal baseline LDH levels vs those with elevated LDH levels at baseline (43% vs 16%). Among patients with normal baseline LDH levels and < 3 organ sites with metastases, the 5-year PFS and OS rates were 31% and 55%, respectively. In addition, exploratory analyses will be performed to characterize subgroup(s) of patients most likely to experience long-term benefit. Of 299 patients who received subsequent anticancer therapy following treatment with D+T, 151 (51%) received an anti–CTLA-4 therapy and 102 (34%) received an anti–PD-1 therapy. The safety profile of D+T was as previously reported, and no new safety signals were observed. No treatment-related deaths were reported. Conclusions: First-line treatment with D+T leads to durable long-term benefit in many patients with BRAF V600–mutant unresectable or metastatic melanoma. Clinical trial information: NCT01584648; NCT01597908.
- Published
- 2019
39. Circulating tumor DNA (ctDNA) kinetics to predict survival in patients (pts) with unresectable or metastatic melanoma treated with dabrafenib (D) or D + trametinib (T)
- Author
-
Georgina V. Long, Paul Nathan, Mahrukh M. Syeda, David Polsky, Michael A. Davies, Eduard Gasal, Dirk Schadendorf, Jean-Jacques Grob, Mahtab Marker, Keith T. Flaherty, Caroline Robert, Antoni Ribas, Jan C. Brase, Matthew Squires, Jennifer M. Wiggins, and Broderick Corless
- Subjects
Trametinib ,Cancer Research ,Prognostic factor ,Metastatic melanoma ,business.industry ,Medizin ,Dabrafenib ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,Oncology ,chemistry ,Circulating tumor DNA ,030220 oncology & carcinogenesis ,Lactate dehydrogenase ,medicine ,Cancer research ,In patient ,business ,030215 immunology ,medicine.drug ,Advanced melanoma - Abstract
9510 Background: There are no validated blood-based biomarkers to monitor efficacy in pts with advanced melanoma. Lactate dehydrogenase (LDH) is an established prognostic factor; however, it is not normally used to inform treatment decisions. ctDNA at baseline (BL) is associated with a poor prognosis in pts treated with BRAF inhibitors, but no studies have examined the association between serial changes in ctDNA and survival after BRAF and/or MEK inhibitor therapy. Methods: We measured BRAF V600E/K ctDNA at BL and wk 4 in plasma samples from a pooled population of pts with unresectable or metastatic melanoma treated with D or D+T in the phase 3 COMBI-d trial (NCT01584648). We used mutation-specific droplet digital PCR assays; ctDNA results were categorized as positive/negative (pos/neg) using an analytically validated detection threshold of 0.25 copies/mL. Progression-free (PFS) and overall survival (OS) were analyzed in all pts and by BL LDH level (> or < upper limit of normal). Results: BL ctDNA was detectable in 320/345 pts (92.7%) and was not associated with survival. Nearly all pts had a considerable drop in ctDNA after 4 wks of therapy; 201 pts had paired samples (BL and wk 4) and detectable ctDNA at BL. In 80/201 pts (40%) whose ctDNA changed from pos at BL to neg at wk 4, PFS and OS were prolonged vs in 121/201 (60%) whose ctDNA remained pos (median PFS, 12.9 [95% CI, 9.2-20.2] mo vs 7.1 [5.5-8.9] mo; HR, 0.55 [0.39-0.76]; P = .0003; median OS, 28.2 [20.5-48.8] mo vs 14.6 [11.8-18.7] mo; HR, 0.56 [0.40-0.79]; P = .0007). Undetectable ctDNA at wk 4 was associated with prolonged PFS and OS, especially in pts with high BL LDH (Table). Conclusions: Particularly in pts with high LDH, on-treatment ctDNA monitoring may be helpful for early identification of pts likely to benefit from D or D+T. All ctDNA Samples at Wk 4. Clinical trial information: NCT01584648. [Table: see text]
- Published
- 2019
40. Association between baseline disease characteristics and relapse-free survival (RFS) in patients (pts) with BRAF V600-mutant resected stage III melanoma treated with adjuvant dabrafenib (D) + trametinib (T) or placebo (PBO)
- Author
-
Jacob Schachter, Dirk Schadendorf, Eduard Gasal, Laurent Mortier, Marta Nyakas, Egbert de Jong, Caroline Dutriaux, Reinhard Dummer, Mario Santinami, Georgina V. Long, John M. Kirkwood, Mario Mandalà, Victoria Atkinson, Vanna Chiarion-Sileni, Andrew Haydon, Caroline Robert, Christine-Elke Ortmann, James Larkin, Richard F. Kefford, and Axel Hauschild
- Subjects
Trametinib ,Cancer Research ,medicine.medical_specialty ,business.industry ,medicine.medical_treatment ,Mutant ,Hazard ratio ,Medizin ,Dabrafenib ,Placebo ,Gastroenterology ,03 medical and health sciences ,0302 clinical medicine ,Oncology ,030220 oncology & carcinogenesis ,Internal medicine ,medicine ,In patient ,Stage III melanoma ,business ,Adjuvant ,030215 immunology ,medicine.drug - Abstract
9582 Background: In the COMBI-AD trial (NCT01682083), 12 mo of adjuvant D+T led to significant improvement of RFS vs PBO (hazard ratio [HR], 0.47; P < .001) in pts with resected BRAF V600–mutant stage III melanoma; 3- and 4-year RFS rates were 59% and 54%, respectively. Previous results demonstrated consistent treatment benefit across baseline disease stage according to AJCC edition 7 or 8. Here, we further explored the association between baseline disease characteristics and RFS to identify pt subgroups likely to benefit from adjuvant treatment. Methods: Randomized pts with completely resected BRAF V600E/K–mutant stage III melanoma received 12 mo of adjuvant D (150 mg BID) + T (2 mg QD) or PBO. Within each subgroup, predictive value was explored using Kaplan-Meier analysis, and HRs were calculated using a Pike estimator. Results: Minimum follow-up was 40 mo for 870 enrolled pts (D+T, 438; PBO, 432). Kaplan-Meier analysis demonstrated treatment benefit across all subgroups analyzed. Assessment of RFS by extent of primary tumor (T stage) showed consistent benefit favoring D+T vs PBO (HR [95% CI]; T1, 0.42 [0.25-0.70]; T2, 0.51 [0.34-0.76]; T3, 0.55 [0.39-0.77]; T4, 0.42 [0.29-0.60]). HRs by nodal burden (N stage) also showed consistent treatment benefit (N1, 0.52 [95% CI, 0.37-0.72]; N2, 0.38 [95% CI, 0.28-0.53]; N3, 0.58 [95% CI, 0.41-0.83]). Substantial treatment benefit was observed in pts with baseline in-transit metastases (HR, 0.45 [95% CI, 0.24-0.82]) and those with no in-transit metastases detected at baseline (HR, 0.49 [95% CI, 0.40-0.60]). When RFS was assessed according to melanoma presentation, treatment benefit favoring D+T vs PBO was observed in pts with superficial spreading melanoma (HR, 0.48 [95% CI, 0.35-0.66]) and those with nodular melanoma (HR, 0.53 [95% CI, 0.37-0.75]). Conclusions: These results confirm earlier findings showing that treatment benefit with adjuvant D+T vs PBO is independent of baseline factors. Clinical trial information: NCT01682083.
- Published
- 2019
41. Tumor microenvironment (TME), longitudinal biomarker changes, and clinical outcome in patients (pts) with advanced BRAF V600–mutant melanoma treated with first-line spartalizumab (S) + dabrafenib (D) + trametinib (T)
- Author
-
Daniel Gusenleitner, Paolo A. Ascierto, Dirk Schadendorf, Naoya Yamazaki, Paul Nathan, Céleste Lebbé, Erika Richtig, Caroline Robert, Hussein Abdul-Hassan Tawbi, Jan C. Brase, Victoria Atkinson, Mario Mandalà, Catarina D. Campbell, Georgina V. Long, Eduard Gasal, Antoni Ribas, Reinhard Dummer, Ana Arance, and Keith T. Flaherty
- Subjects
Trametinib ,Cancer Research ,Tumor microenvironment ,business.industry ,Melanoma ,Mutant ,Medizin ,Dabrafenib ,medicine.disease ,03 medical and health sciences ,0302 clinical medicine ,Oncology ,030220 oncology & carcinogenesis ,Mutation (genetic algorithm) ,Gene expression ,Cancer research ,Medicine ,In patient ,business ,030215 immunology ,medicine.drug - Abstract
9515 Background: Although pts with both low tumor mutation burden (TMB) and T-cell–inflamed gene expression profiles (TI-GEPs) usually have poor outcomes with anti–PD-1 therapy, an analysis in the adjuvant melanoma setting suggested that these pts benefited from adjuvant D+T therapy. Here we analyze TMB/TI-GEPs and other biomarkers in pts receiving a combination of anti–PD-1 and D+T therapy. Methods: The phase 3 COMBI-i study (NCT02967692) is evaluating S in combination with D+T in previously untreated pts with BRAF V600–mutant unresectable/metastatic melanoma. In the safety run-in (part [p] 1) and biomarker (p2) cohorts, blood/tissue samples were collected at baseline (BL), after 2-3 and 8-12 wk of treatment, and at disease progression. TMB/circulating tumor DNA (ctDNA) and TI-GEPs were examined by targeted DNA-seq and RNA-seq, respectively. Results: At data cutoff, 6 of 22 pts with DNA- and RNA-seq data available had a PFS event. At BL, these pts had low TMB, low TI-GEPs (4 of 6), or high levels of immunosuppressive TME signatures (eg, fibroblast, M2 macrophages) vs pts without a PFS event. Elevated BL ctDNA was significantly associated with PFS events ( P< .001). Pts with a complete response (CR) on S+D+T had significantly lower levels of BL immunosuppressive TME signatures (eg, M2 macrophages; P< .01) than pts without a CR. We observed a consistent increase in TI-GEPs and decrease in MAPK pathway activity score (MPAS) from BL to biopsy at 2-3 wk in all pts regardless of subsequent progression. Pts with a PFS event and available longitudinal biomarker data were characterized by a subsequent decrease in TI-GEPs and an increase in MPAS per the 8- to 12- wk biopsy sample. Conclusions: These results suggest that S+D+T had an early impact on tumor cells and the TME, potentially promoting antitumor activity. The majority of PFS events occurred in the TMB-low/TI-GEP-low subgroup. An immunosuppressive TME might preclude early CRs. The predictive implications of coupling TMB/GEP subgroups with other TME marker subgroups need further validation. The randomized placebo-controlled p3 of COMBI-i is ongoing. Clinical trial information: NCT02967692.
- Published
- 2019
42. Longer Follow-Up Confirms Relapse-Free Survival Benefit With Adjuvant Dabrafenib Plus Trametinib in Patients With Resected BRAF V600–Mutant Stage III Melanoma
- Author
-
John M. Kirkwood, James Larkin, Mario Mandalà, Richard F. Kefford, Tomas Haas, Vanna Chiarion-Sileni, Caroline Robert, Kohinoor Dasgupta, Axel Hauschild, Mario Santinami, Mark Shilkrut, Caroline Dutriaux, Eduard Gasal, Dirk Schadendorf, Georgina V. Long, Jacob Schachter, Andrew Haydon, Laurent Mortier, Ruth Plummer, Victoria Atkinson, Marta Nyakas, Thierry Lesimple, Reinhard Dummer, University of Zurich, and Long, Georgina V
- Subjects
Male ,0301 basic medicine ,Oncology ,Cancer Research ,Internationality ,Skin Neoplasms ,Time Factors ,Medizin ,0302 clinical medicine ,Antineoplastic Combined Chemotherapy Protocols ,Oximes ,Clinical endpoint ,1306 Cancer Research ,Stage (cooking) ,Melanoma ,Trametinib ,Hazard ratio ,Age Factors ,Imidazoles ,10177 Dermatology Clinic ,Middle Aged ,Treatment Outcome ,030220 oncology & carcinogenesis ,Female ,2730 Oncology ,Rapid Communication ,medicine.drug ,Adult ,Proto-Oncogene Proteins B-raf ,medicine.medical_specialty ,Pyridones ,610 Medicine & health ,Pyrimidinones ,Placebo ,Disease-Free Survival ,Drug Administration Schedule ,03 medical and health sciences ,Sex Factors ,Adjuvants, Immunologic ,Double-Blind Method ,Internal medicine ,Correspondence ,medicine ,Humans ,Dose-Response Relationship, Drug ,business.industry ,Cancer ,Dabrafenib ,medicine.disease ,Clinical trial ,030104 developmental biology ,business ,Follow-Up Studies - Abstract
Purpose Dabrafenib plus trametinib improved relapse-free survival (RFS) versus placebo (hazard ratio [HR], 0.47; P < .001) in patients with resected BRAF V600–mutant stage III melanoma (BRF115532; COMBI-AD; ClinicalTrials.gov identifier: NCT01682083). We present an updated RFS analysis on the basis of extended study follow-up and a cure-rate model analysis to estimate the fraction of patients expected to remain relapse free long term. Methods In this phase III trial, patients with resected BRAF V600–mutant stage III melanoma were randomly assigned to 12 months of adjuvant dabrafenib plus trametinib versus placebo. We report updated RFS (primary end point) and distant metastasis–free survival. RFS was also analyzed by subgroups defined by baseline disease stage (American Joint Committee on Cancer 7th and 8th editions), nodal metastatic burden, and ulceration status. The fraction of patients who remained relapse free long term was estimated using a Weibull mixture cure-rate model. Results At median follow-up of 44 months (dabrafenib plus trametinib) and 42 months (placebo), 3- and 4-year RFS rates were 59% (95% CI, 55% to 64%) and 54% (95% CI, 49% to 59%) in the dabrafenib plus trametinib arm and 40% (95% CI, 35% to 45%) and 38% (95% CI, 34% to 44%) in the placebo arm, respectively (HR, 0.49; 95% CI, 0.40 to 0.59). Distant metastasis–free survival also favored dabrafenib plus trametinib (HR, 0.53; 95% CI, 0.42 to 0.67). The estimated cure rate was 54% (95% CI, 49% to 59%) in the dabrafenib plus trametinib arm compared with 37% (95% CI, 32% to 42%) in the placebo arm. Subgroup analysis of RFS demonstrated similar treatment benefit regardless of baseline factors, including disease stage, nodal metastatic burden, and ulceration. Conclusion Longer follow-up confirmed RFS benefit with dabrafenib plus trametinib. Subgroup analysis suggested that dabrafenib plus trametinib benefited patients regardless of baseline factors.
- Published
- 2018
43. BRAF-mutant ctDNA predicts outcomes
- Author
-
Jean-Jacques Grob, Mahrukh M. Syeda, Antoni Ribas, Georgina V. Long, Mahtab Marker, Broderick Corless, Dirk Schadendorf, Keith T. Flaherty, James Garrett, David Polsky, Eduard Gasal, Matthew Squires, Caroline Robert, Jan C. Brase, Jennifer M. Wiggins, Michael A. Davies, and Paul Nathan
- Subjects
Male ,0301 basic medicine ,Oncology ,Mutant ,Medizin ,Phases of clinical research ,Bioinformatics ,Circulating Tumor DNA ,0302 clinical medicine ,Oximes ,Antineoplastic Combined Chemotherapy Protocols ,Medicine ,Melanoma ,Cancer ,Trametinib ,screening and diagnosis ,Brain Neoplasms ,MEK inhibitor ,Hazard ratio ,Imidazoles ,Middle Aged ,Prognosis ,Survival Rate ,Detection ,030220 oncology & carcinogenesis ,Female ,4.2 Evaluation of markers and technologies ,medicine.drug ,Proto-Oncogene Proteins B-raf ,medicine.medical_specialty ,Pyridones ,Clinical Trials and Supportive Activities ,Oncology and Carcinogenesis ,MEDLINE ,Pyrimidinones ,Article ,03 medical and health sciences ,Text mining ,Double-Blind Method ,Clinical Research ,Internal medicine ,Humans ,Oncology & Carcinogenesis ,Survival rate ,Aged ,Performance status ,business.industry ,Dabrafenib ,medicine.disease ,Good Health and Well Being ,030104 developmental biology ,Cancer genetics ,business ,Follow-Up Studies - Abstract
BackgroundMelanoma lacks validated blood-based biomarkers for monitoring and predicting treatment efficacy. Cell-free circulating tumour DNA (ctDNA) is a promising biomarker; however, various detection methods have been used, and, to date, no large studies have examined the association between serial changes in ctDNA and survival after BRAF, MEK, or BRAF plus MEK inhibitor therapy. We aimed to evaluate whether baseline ctDNA concentrations and kinetics could predict survival outcomes.MethodsIn this clinical validation study, we used analytically validated droplet digital PCR assays to measure BRAFV600-mutant ctDNA in pretreatment and on-treatment plasma samples from patients aged 18 years or older enrolled in two clinical trials. COMBI-d (NCT01584648) was a double-blind, randomised phase 3 study of dabrafenib plus trametinib versus dabrafenib plus placebo in previously untreated patients with BRAFV600 mutation-positive unresectable or metastatic melanoma. Patients had an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1. COMBI-MB (NCT02039947) was an open-label, non-randomised, phase 2 study evaluating dabrafenib plus trametinib in patients with BRAFV600 mutation-positive metastatic melanoma and brain metastases. Patients in cohort A of COMBI-MB had asymptomatic brain metastases, no previous local brain-directed therapy, and an ECOG performance status of 0 or 1. Biomarker analysis was a prespecified exploratory endpoint in both trials and performed in the intention-to-treat populations in COMBI-d and COMBI-MB. We investigated the association between mutant copy number (baseline or week 4 or zero conversion status) and efficacy endpoints (progression-free survival, overall survival, and best overall response). We used Cox models, Kaplan-Meier plots, and log-rank tests to explore the association of pretreatment ctDNA concentrations with progression-free survival and overall survival. The effect of additional prognostic variables such as lactate dehydrogenase was also investigated in addition to the mutant copy number.FindingsIn COMBI-d, pretreatment plasma samples were available from 345 (82%) of 423 patients and on-treatment (week 4) plasma samples were available from 224 (53%) of 423 patients. In cohort A of COMBI-MB, pretreatment and on-treatment samples were available from 38 (50%) of 76 patients with intracranial and extracranial metastatic melanoma. ctDNA was detected in pretreatment samples from 320 (93%) of 345 patients (COMBI-d) and 34 (89%) of 38 patients (COMBI-MB). When assessed as a continuous variable, elevated baseline BRAFV600 mutation-positive ctDNA concentration was associated with worse overall survival outcome (hazard ratio [HR] 1·13 [95% CI 1·09-1·18], p
- Published
- 2021
44. LGG-49. SAFETY AND EFFICACY OF TRAMETINIB (T) MONOTHERAPY AND DABRAFENIB + TRAMETINIB (D+T) COMBINATION THERAPY IN PEDIATRIC PATIENTS WITH BRAF V600-MUTANT LOW-GRADE GLIOMA (LGG)
- Author
-
Lindsay Kilburn, Kenneth J. Cohen, Eduard Gasal, Darren Hargrave, Isabelle Aerts, Elizabeth Fox, Birgit Geoerger, Karen Wright, James A. Whitlock, Eric Bouffet, Jeea Choi, Mark W. Russo, Cynthia Wetmore, Santhosh A. Upadhyaya, and Christopher L. Moertel
- Subjects
Trametinib ,Oncology ,Cancer Research ,medicine.medical_specialty ,Combination therapy ,business.industry ,Mutant ,Low Grade Glioma ,Dabrafenib ,Internal medicine ,medicine ,AcademicSubjects/MED00300 ,AcademicSubjects/MED00310 ,Low-Grade Glioma ,Neurology (clinical) ,business ,medicine.drug - Abstract
BACKGROUND Children with BRAF V600-mutant LGG have suboptimal response to standard chemotherapy. Previously, D (BRAF V600 inhibitor) monotherapy has demonstrated clinical benefit in this population. We report interim analysis results of pediatric patients with recurrent/refractory BRAF V600-mutant LGG treated with either T (MEK1/2 inhibitor) monotherapy or D+T combination therapy. METHODS This is a 4-part, open-label, multicenter, phase I/II study (NCT02124772) in pediatric patients ( RESULTS Of 49 pediatric patients with BRAF V600-mutant LGG (T, n=13; D+T, n=36) enrolled, pooled efficacy data was available for both treatments while safety data was available for 30 patients (T, n=10; D+T, n=20). Most patients (n=8/10) receiving T monotherapy withdrew/discontinued the treatment in contrast to 3/20 in the D+T group. Pyrexia occurred in 50% of patients (n=5/10) in the monotherapy group and was a frequent AE in the combination group (75%; n=15/20). Objective response rate per independent review was 15% (95% CI, 2%–45%) with T monotherapy and 25% (95% CI, 12%–42%) with D+T combination therapy. Seven patients (54%) on monotherapy and 33 patients (92%) on combination therapy had stable disease or better. CONCLUSION In pediatric patients with previously treated BRAF V600-mutant LGG, T monotherapy and D+T combination therapy demonstrated clinical activity, with pyrexia being a common AE.
- Published
- 2020
45. Dabrafenib plus trametinib in patients with BRAFV600E-mutated biliary tract cancer – Authors' reply
- Author
-
Vivek Subbiah, Eduard Gasal, Ulrik Lassen, Zev A. Wainberg, and Paul Burgess
- Subjects
Trametinib ,Biliary tract neoplasm ,Biliary tract cancer ,Oncology ,business.industry ,medicine ,Cancer research ,Dabrafenib ,In patient ,business ,medicine.drug - Published
- 2020
46. Characteristics of Patients With a Complete Response Treated With Dabrafenib + Trametinib Combination Therapy: Findings From Pooled COMBI-d and COMBI-v 5-Year Analysis
- Author
-
Caroline Robert, Daniil Stroyakovskiy, Axel Hauschild, Michael Davies, Jacob Schachter, Boguslawa Karaszewska, Claus Garbe, Paul Burgess, Dirk Schadendorf, Antoni Ribas, Evgeny Levchenko, Paul Nathan, Monique Tan, Eduard Gasal, Jean J. Grob, Vanna Chiarion Sileni, Igor Bondarenko, Keith T. Flaherty, and Georgina V. Long
- Subjects
Oncology ,Trametinib ,Cancer survivorship ,medicine.medical_specialty ,Patient Navigator ,Combination therapy ,business.industry ,Melanoma ,Patient characteristics ,Dabrafenib ,medicine.disease ,Internal medicine ,medicine ,business ,Complete response ,medicine.drug - Abstract
not available.
- Published
- 2020
47. Administration and Handling of Talimogene Laherparepvec: An Intralesional Oncolytic Immunotherapy for Melanoma
- Author
-
Brianna Hoffner, Gail Iodice, and Eduard Gasal
- Subjects
Oncolytic Virotherapy ,medicine.medical_specialty ,business.industry ,medicine.medical_treatment ,Data synthesis ,Melanoma ,Context (language use) ,Immunotherapy ,medicine.disease ,Surgery ,Oncolytic virus ,Clinical trial ,Oncolytic Viruses ,03 medical and health sciences ,0302 clinical medicine ,030220 oncology & carcinogenesis ,medicine ,Humans ,Outpatient clinic ,030212 general & internal medicine ,Talimogene laherparepvec ,business - Abstract
Purpose/objectives To describe the administration and handling requirements of oncolytic viruses in the context of talimogene laherparepvec (Imlygic™), a first-in-class oncolytic immunotherapy. . Data sources Study procedures employed in clinical trials, in particular the OPTiM study. . Data synthesis Evaluation of nursing considerations for administration of talimogene laherparepvec. . Conclusions Talimogene laherparepvec is administered through a series of intralesional injections into cutaneous, subcutaneous, or nodal tumors (with ultrasound guidance as needed) during an outpatient clinic visit. A single insertion point is recommended; however, multiple insertion points are acceptable if the tumor radius exceeds the needle's radial reach. Talimogene laherparepvec must be evenly distributed throughout the tumor through each insertion site. Talimogene laherparepvec requires storage at -90°C to -70°C and, once thawed, should be administered immediately or stored in its original vial and carton and protected from light in a refrigerator (2°C to 8°C). . Implications for nursing Because talimogene laherparepvec can be administered in the outpatient setting, nurses will be pivotal for appropriate integration and administration of this unique and effective therapy.
- Published
- 2016
48. LBA43 Spartalizumab plus dabrafenib and trametinib (Sparta-DabTram) in patients (pts) with previously untreated BRAF V600–mutant unresectable or metastatic melanoma: Results from the randomized part 3 of the phase III COMBI-i trial
- Author
-
C. Dutriaux, Aisha Masood, P.A. Ascierto, Antoni Ribas, Keith T. Flaherty, Eduard Gasal, Jan C. Brase, Paul Lorigan, H.A. Tawbi, Steven H. Green, Pier Francesco Ferrucci, Mario Mandalà, C. Robert, Piotr Rutkowski, O. Leonov, Georgina V. Long, Paul Nathan, Dirk Schadendorf, Tomas Haas, and Reinhard Dummer
- Subjects
Trametinib ,Oncology ,medicine.medical_specialty ,Metastatic melanoma ,business.industry ,Mutant ,Dabrafenib ,Hematology ,Internal medicine ,Medicine ,In patient ,business ,medicine.drug - Published
- 2020
49. 561P Phase Ib study of ribociclib (R) + trametinib (T) in patients (pts) with metastatic/advanced solid tumours
- Author
-
Filip Janku, L. Sandalic, Jennifer L. Spratlin, C-C. Lin, Marwan Fakih, Julia Beck, A.M. Abdelhady, Jayesh Desai, F.Y.F.L. De Vos, T. Cascella, Aislyn Boran, E. Van Cutsem, Eduard Gasal, Geoffrey I. Shapiro, Jaime R. Merchan, and Patricia LoRusso
- Subjects
Oncology ,Trametinib ,medicine.medical_specialty ,business.industry ,Internal medicine ,Phase (matter) ,medicine ,In patient ,Ribociclib ,Hematology ,business - Published
- 2020
50. Updated overall survival (OS) and genomic analysis from a single-arm phase II study of dabrafenib (D) + trametinib (T) in patients (pts) with BRAF V600E mutant (Mut) metastatic non-small cell lung cancer (NSCLC)
- Author
-
Benjamin Besse, Julien Mazieres, Eduard Gasal, Shirong Zhang, Bruce E. Johnson, Tae Min Kim, Elisabeth Quoix, Monique Tan, Harry J.M. Groen, Libero Santarpia, Christina S. Baik, Liza C. Villaruz, Fabrice Barlesi, David Planchard, Sayed M S Hashemi, Ronan J. Kelly, and Pierre Jean Souquet
- Subjects
Oncology ,Trametinib ,Cancer Research ,medicine.medical_specialty ,business.industry ,Mutant ,Phases of clinical research ,non-small cell lung cancer (NSCLC) ,Dabrafenib ,medicine.disease ,BRAF V600E ,03 medical and health sciences ,0302 clinical medicine ,030220 oncology & carcinogenesis ,Internal medicine ,Cohort ,medicine ,In patient ,business ,030215 immunology ,medicine.drug - Abstract
9593 Background: The phase II multicenter, open label study, which evaluated efficacy and safety of D+T in pretreated (cohort B) and treatment (tx)-naive (cohort C) pts with BRAF V600E mut metastatic NSCLC. The results of the primary analysis have been reported. Here, we present an updated survival and genomic analysis data for cohorts B and C. Methods: Tx-naïve (n=36) and pretreated (n=57) pts received D 150 mg twice daily + T 2 mg daily. Primary objective: ORR, secondary objectives: PFS, DOR, OS, safety, tolerability and PK of D+T. Tumor samples were centrally tested using a NGS cancer targeted panel (Oncomine Dx Target test, ThermoFisher Scientific). KM curves and Cox regression models were used to evaluate potential associations between baseline genomic landscape and pt efficacy endpoints. Results: As of June 22, 2019, median (m) follow-up was 16.3 mo in tx-naïve pts and 16.6 mo in pretreated pts. mOS was 17.3 mo (95% CI: 12.3, 40.2; 3 yr OS: 40%) and 18.2 mo (95% CI: 14.3, 28.6; 3 yr OS: 33%) with 14/36 and 11/57 pts alive in tx naïve and pretreated pts respectively. Detailed efficacy results are presented in table. 57/62 tumor samples retrieved from 93 pts were centrally confirmed to have BRAF V600E mut; 5 non-confirmed BRAF tumors (3 pts had PR) were positive for c-MET T1010I, KRAS G12V, ALK fusion and 2 JAK3 S493C with mPFS of 13.8 mo while OS was NE due to limited data points. Eleven pts (18%) had concomitant somatic mutations and/or genetic alterations in addition to BRAF V600E mut: 4 had alterations within PI3K pathway4 had concomitant mutations at IDH1 R132X, and 3 pts had additional mutations at BRAF G466V, KRAS G13C and a cMET exon 14 skipping, respectively. Pts whose tumors had concomitant genetic alterations, particularly in PI3K pathway, showed a trend towards decreased PFS and OS. Safety profile was similar to previous reported results. Conclusions: This update of BRF113928 study reported improved and durable OS rates with combination D+T in BRAF V600E mut NSCLC pts. Co-occurring genetic alterations might influence clinical outcomes of such pts. Further validation is ongoing to corroborate current genomic findings. Clinical trial information: NCT01336634 . [Table: see text]
- Published
- 2020
Catalog
Discovery Service for Jio Institute Digital Library
For full access to our library's resources, please sign in.