IMPemBra: a phase 2 study comparing pembrolizumab with intermittent/short-term dual MAPK pathway inhibition plus pembrolizumab in patients with melanoma harboring the BRAFV600 mutation
Background Continuous combination of MAPK pathway inhibition (MAPKi) and anti-programmed death-(ligand) 1 (PD-(L)1) showed high response rates, but only limited improvement in progression-free survival (PFS) at the cost of a high frequency of treatment-related adverse events (TRAE) in patients with...
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| Format: | Article |
| Language: | English |
| Published: |
BMJ Publishing Group
2023-07-01
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| Series: | Journal for ImmunoTherapy of Cancer |
| Online Access: | https://jitc.bmj.com/content/11/7/e006821.full |
| _version_ | 1797768217059393536 |
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| author | Annegien Broeks Sofie Wilgenhof John B A G Haanen Karolina Sikorska Christian U Blank Judith M Versluis Jan Willem B de Groot Esmee P Hoefsmit Elisa A Rozeman Petros Dimitriadis Aysegul Sari Daan van den Broek Disha Rao Ruben Lacroix Lindsay G Grijpink-Ongering Marta Lopez-Yurda Birthe C Heeres Bart A van de Wiel Claudie Flohil Stijn W T P J Heijmink Marieke A Vollebergh Johannes V van Thienen |
| author_facet | Annegien Broeks Sofie Wilgenhof John B A G Haanen Karolina Sikorska Christian U Blank Judith M Versluis Jan Willem B de Groot Esmee P Hoefsmit Elisa A Rozeman Petros Dimitriadis Aysegul Sari Daan van den Broek Disha Rao Ruben Lacroix Lindsay G Grijpink-Ongering Marta Lopez-Yurda Birthe C Heeres Bart A van de Wiel Claudie Flohil Stijn W T P J Heijmink Marieke A Vollebergh Johannes V van Thienen |
| author_sort | Annegien Broeks |
| collection | DOAJ |
| description | Background Continuous combination of MAPK pathway inhibition (MAPKi) and anti-programmed death-(ligand) 1 (PD-(L)1) showed high response rates, but only limited improvement in progression-free survival (PFS) at the cost of a high frequency of treatment-related adverse events (TRAE) in patients with BRAFV600-mutated melanoma. Short‐term MAPKi induces T-cell infiltration in patients and is synergistic with anti-programmed death-1 (PD‐1) in a preclinical melanoma mouse model. The aim of this phase 2b trial was to identify an optimal regimen of short-term MAPKi with dabrafenib plus trametinib in combination with pembrolizumab.Methods Patients with treatment-naïve BRAFV600E/K-mutant advanced melanoma started pembrolizumab 200 mg every 3 weeks. In week 6, patients were randomized to continue pembrolizumab only (cohort 1), or to receive, in addition, intermittent dabrafenib 150 mg two times per day plus trametinib 2 mg one time per day for two cycles of 1 week (cohort 2), two cycles of 2 weeks (cohort 3), or continuously for 6 weeks (cohort 4). All cohorts continued pembrolizumab for up to 2 years. Primary endpoints were safety and treatment-adherence. Secondary endpoints were objective response rate (ORR) at week 6, 12, 18 and PFS.Results Between June 2016 and August 2018, 33 patients with advanced melanoma have been included and 32 were randomized. Grade 3–4 TRAE were observed in 12%, 12%, 50%, and 63% of patients in cohort 1, 2, 3, and 4, respectively. All planned targeted therapy was given in 88%, 63%, and 38% of patients in cohort 2, 3, and 4. ORR at week 6, 12, and 18 were 38%, 63%, and 63% in cohort 1; 25%, 63%, and 75% in cohort 2; 25%, 50%, and 75% in cohort 3; and 0%, 63%, and 50% in cohort 4. After a median follow-up of 43.5 months, median PFS was 10.6 months for pembrolizumab monotherapy and not reached for patients treated with pembrolizumab and intermittent dabrafenib and trametinib (p=0.17). The 2-year and 3-year landmark PFS were both 25% for cohort 1, both 63% for cohort 2, 50% and 38% for cohort 3 and 75% and 60% for cohort 4.Conclusions The combination of pembrolizumab plus intermittent dabrafenib and trametinib seems more feasible and tolerable than continuous triple therapy. The efficacy is promising and appears to be favorable over pembrolizumab monotherapy.Trial registration number NCT02625337. |
| first_indexed | 2024-03-12T20:50:14Z |
| format | Article |
| id | doaj.art-85f4bb454d4548b7b0eddc4aff9da5e2 |
| institution | Directory Open Access Journal |
| issn | 2051-1426 |
| language | English |
| last_indexed | 2024-03-12T20:50:14Z |
| publishDate | 2023-07-01 |
| publisher | BMJ Publishing Group |
| record_format | Article |
| series | Journal for ImmunoTherapy of Cancer |
| spelling | doaj.art-85f4bb454d4548b7b0eddc4aff9da5e22023-08-01T03:50:08ZengBMJ Publishing GroupJournal for ImmunoTherapy of Cancer2051-14262023-07-0111710.1136/jitc-2023-006821IMPemBra: a phase 2 study comparing pembrolizumab with intermittent/short-term dual MAPK pathway inhibition plus pembrolizumab in patients with melanoma harboring the BRAFV600 mutationAnnegien Broeks0Sofie Wilgenhof1John B A G Haanen2Karolina Sikorska3Christian U Blank4Judith M Versluis5Jan Willem B de Groot6Esmee P Hoefsmit7Elisa A Rozeman8Petros Dimitriadis9Aysegul Sari10Daan van den Broek11Disha Rao12Ruben Lacroix13Lindsay G Grijpink-Ongering14Marta Lopez-Yurda15Birthe C Heeres16Bart A van de Wiel17Claudie Flohil18Stijn W T P J Heijmink19Marieke A Vollebergh20Johannes V van Thienen21Core Facility and Biobanking, Netherlands Cancer Institute, Amsterdam, The NetherlandsDepartment of Medical Oncology, Netherlands Cancer Institute, Amsterdam, The NetherlandsDepartment of Medical Oncology, Netherlands Cancer Institute, Amsterdam, The NetherlandsDepartment of Biometrics, Netherlands Cancer Institute, Amsterdam, The NetherlandsDepartment of Medical Oncology, Netherlands Cancer Institute, Amsterdam, The NetherlandsDepartment of Medical Oncology, Netherlands Cancer Institute, Amsterdam, The NetherlandsIsala Oncology Center, Isala, Zwolle, The NetherlandsDivision of Molecular Oncology and Immunology, Netherlands Cancer Institute, Amsterdam, The NetherlandsDepartment of Medical Oncology, Netherlands Cancer Institute, Amsterdam, The NetherlandsDivision of Molecular Oncology and Immunology, Netherlands Cancer Institute, Amsterdam, The NetherlandsDepartment of Biometrics, Netherlands Cancer Institute, Amsterdam, The NetherlandsDepartment of Laboratory Medicine, Netherlands Cancer Institute, Amsterdam, The NetherlandsDivision of Molecular Oncology and Immunology, Netherlands Cancer Institute, Amsterdam, The NetherlandsDivision of Molecular Oncology and Immunology, Netherlands Cancer Institute, Amsterdam, The NetherlandsDepartment of Biometrics, Netherlands Cancer Institute, Amsterdam, The NetherlandsDepartment of Biometrics, Netherlands Cancer Institute, Amsterdam, The NetherlandsDepartment of Radiology, Netherlands Cancer Institute, Amsterdam, The NetherlandsDepartment of Pathology, Netherlands Cancer Institute, Amsterdam, The NetherlandsDepartment of Pathology, Netherlands Cancer Institute, Amsterdam, The NetherlandsDepartment of Radiology, Netherlands Cancer Institute, Amsterdam, The NetherlandsDepartment of Medical Oncology, Netherlands Cancer Institute, Amsterdam, The NetherlandsDepartment of Medical Oncology, Netherlands Cancer Institute, Amsterdam, The NetherlandsBackground Continuous combination of MAPK pathway inhibition (MAPKi) and anti-programmed death-(ligand) 1 (PD-(L)1) showed high response rates, but only limited improvement in progression-free survival (PFS) at the cost of a high frequency of treatment-related adverse events (TRAE) in patients with BRAFV600-mutated melanoma. Short‐term MAPKi induces T-cell infiltration in patients and is synergistic with anti-programmed death-1 (PD‐1) in a preclinical melanoma mouse model. The aim of this phase 2b trial was to identify an optimal regimen of short-term MAPKi with dabrafenib plus trametinib in combination with pembrolizumab.Methods Patients with treatment-naïve BRAFV600E/K-mutant advanced melanoma started pembrolizumab 200 mg every 3 weeks. In week 6, patients were randomized to continue pembrolizumab only (cohort 1), or to receive, in addition, intermittent dabrafenib 150 mg two times per day plus trametinib 2 mg one time per day for two cycles of 1 week (cohort 2), two cycles of 2 weeks (cohort 3), or continuously for 6 weeks (cohort 4). All cohorts continued pembrolizumab for up to 2 years. Primary endpoints were safety and treatment-adherence. Secondary endpoints were objective response rate (ORR) at week 6, 12, 18 and PFS.Results Between June 2016 and August 2018, 33 patients with advanced melanoma have been included and 32 were randomized. Grade 3–4 TRAE were observed in 12%, 12%, 50%, and 63% of patients in cohort 1, 2, 3, and 4, respectively. All planned targeted therapy was given in 88%, 63%, and 38% of patients in cohort 2, 3, and 4. ORR at week 6, 12, and 18 were 38%, 63%, and 63% in cohort 1; 25%, 63%, and 75% in cohort 2; 25%, 50%, and 75% in cohort 3; and 0%, 63%, and 50% in cohort 4. After a median follow-up of 43.5 months, median PFS was 10.6 months for pembrolizumab monotherapy and not reached for patients treated with pembrolizumab and intermittent dabrafenib and trametinib (p=0.17). The 2-year and 3-year landmark PFS were both 25% for cohort 1, both 63% for cohort 2, 50% and 38% for cohort 3 and 75% and 60% for cohort 4.Conclusions The combination of pembrolizumab plus intermittent dabrafenib and trametinib seems more feasible and tolerable than continuous triple therapy. The efficacy is promising and appears to be favorable over pembrolizumab monotherapy.Trial registration number NCT02625337.https://jitc.bmj.com/content/11/7/e006821.full |
| spellingShingle | Annegien Broeks Sofie Wilgenhof John B A G Haanen Karolina Sikorska Christian U Blank Judith M Versluis Jan Willem B de Groot Esmee P Hoefsmit Elisa A Rozeman Petros Dimitriadis Aysegul Sari Daan van den Broek Disha Rao Ruben Lacroix Lindsay G Grijpink-Ongering Marta Lopez-Yurda Birthe C Heeres Bart A van de Wiel Claudie Flohil Stijn W T P J Heijmink Marieke A Vollebergh Johannes V van Thienen IMPemBra: a phase 2 study comparing pembrolizumab with intermittent/short-term dual MAPK pathway inhibition plus pembrolizumab in patients with melanoma harboring the BRAFV600 mutation Journal for ImmunoTherapy of Cancer |
| title | IMPemBra: a phase 2 study comparing pembrolizumab with intermittent/short-term dual MAPK pathway inhibition plus pembrolizumab in patients with melanoma harboring the BRAFV600 mutation |
| title_full | IMPemBra: a phase 2 study comparing pembrolizumab with intermittent/short-term dual MAPK pathway inhibition plus pembrolizumab in patients with melanoma harboring the BRAFV600 mutation |
| title_fullStr | IMPemBra: a phase 2 study comparing pembrolizumab with intermittent/short-term dual MAPK pathway inhibition plus pembrolizumab in patients with melanoma harboring the BRAFV600 mutation |
| title_full_unstemmed | IMPemBra: a phase 2 study comparing pembrolizumab with intermittent/short-term dual MAPK pathway inhibition plus pembrolizumab in patients with melanoma harboring the BRAFV600 mutation |
| title_short | IMPemBra: a phase 2 study comparing pembrolizumab with intermittent/short-term dual MAPK pathway inhibition plus pembrolizumab in patients with melanoma harboring the BRAFV600 mutation |
| title_sort | impembra a phase 2 study comparing pembrolizumab with intermittent short term dual mapk pathway inhibition plus pembrolizumab in patients with melanoma harboring the brafv600 mutation |
| url | https://jitc.bmj.com/content/11/7/e006821.full |
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