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  • 1
    Online Resource
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    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: Three-year survival data and translational analyses.
    American Society of Clinical Oncology (ASCO) ; 2022
    In:  Journal of Clinical Oncology Vol. 40, No. 16_suppl ( 2022-06-01), p. 9552-9552
    Details
    In: Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 40, No. 16_suppl ( 2022-06-01), p. 9552-9552
    Abstract: 9552 Background: Continuous combination of MAPK pathway inhibition (MAPKi) and anti-PD-(L)1 showed high response rates, but also high frequency of treatment-related adverse events (TRAE) in BRAFV600-mutated melanoma patients (pts). Short‐time MAPKi already induces T cell infiltration in pts and was synergistic with anti-PD‐1 in a pre-clinical model. This phase 2b trial aimed to identify the optimal duration of MAPKi with dabrafenib + trametinib (D+T) in combination with pembrolizumab (PEM). We have previously shown that no SUSARs were observed, toxicity was related to duration of D+T, and response rates increased after addition of D+T. Here we present 3-year PFS and OS data and results of translational analyses. Methods: In IMPemBra, pts with treatment-naïve BRAFV600E/K mutant advanced melanoma started with PEM 200mg Q3W. After 2 cycles, pts were randomized to continue PEM only (cohort 1) or to receive in addition intermittent dabrafenib 150 mg BID + trametinib 2mg QD for 2 x 1 week (cohort 2), 2 x 2 weeks (cohort 3) or continuous for 6 weeks (cohort 4). All cohorts continued PEM for up to 2 years. Primary endpoints were safety, treatment adherence and immune-activating capacity of the different regimens. Secondary endpoints were objective response rate (ORR) and PFS, OS was an exploratory endpoint. For survival analyses, pts that received D+T (cohort 2-4) were pooled. Results: Thirty-two pts were randomized, 56% were male, 53% had M1c disease and 88% had a LDH level 〈 ULN. No new grade 3-4 TRAE were observed; frequencies were 12%, 12%, 50% and 62% for pts in cohort 1, 2, 3 and 4, respectively. ORRs were 75% in cohort 1 and 2, and 88% in cohort 3 and 4. The frequency of PD1 + CD8 + T cells in peripheral blood decreased slightly during treatment and there were no differences between cohorts. In cohort 1 and 2, an increase in IFNγ signature in tumor biopsies was already observed after 6 weeks of PEM, in cohort 3-4 an increase in IFNγ signature was observed in week 9, after addition of D+T. The same pattern was observed for CD8 + T cell infiltration and PD-L1 expression. After a median follow-up of 43.5 months, the median PFS of pts treated with PEM monotherapy was 10.6 months versus 32.3 months for pts treated with PEM plus D+T (p = 0.19). The 3-year PFS rates were 25.0% and 50.0% respectively. Median OS was 40.5 months in the PEM pts and not reached for pts treated with PEM plus D+T (p = 0.32); 3-year OS rates were 62.5% and 70.8% respectively. Conclusions: IMPemBra demonstrated that short-term addition of intermittent D+T to PEM seems a more feasible, tolerable and an effective alternative for the continuous triple combination. In addition, it gives the opportunity to treat with second line targeted therapy after disease progression. Therefore, this regimen should be considered for further investigation in a larger cohort. Clinical trial information: NCT02625337.
    Type of Medium: Online Resource
    ISSN: 0732-183X , 1527-7755
    URL: Article
    DOI: 10.1200/JCO.2022.40.16_suppl.9552
    RVK:
    XA 52760
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Clinical Oncology (ASCO)
    Publication Date: 2022
    detail.hit.zdb_id: 2005181-5
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  • 2
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    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
    BMJ ; 2023
    In:  Journal for ImmunoTherapy of Cancer Vol. 11, No. 7 ( 2023-07), p. e006821-
    Details
    In: Journal for ImmunoTherapy of Cancer, BMJ, Vol. 11, No. 7 ( 2023-07), p. e006821-
    Abstract: 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 BRAF V600 -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 BRAF V600E/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 .
    Type of Medium: Online Resource
    ISSN: 2051-1426
    URL: Article
    DOI: 10.1136/jitc-2023-006821
    Language: English
    Publisher: BMJ
    Publication Date: 2023
    detail.hit.zdb_id: 2719863-7
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