Phase II study of durvalumab (anti-PD-L1) and trametinib (MEKi) in microsatellite stable (MSS) metastatic colorectal cancer (mCRC)
Background Monotherapy with immune checkpoint blockade is ineffective for patients (pts) with microsatellite stable (MSS) metastatic colorectal cancer (mCRC). This study investigates whether the combination of trametinib (T) with durvalumab (D) can alter the immune tumor microenvironment (TME) by su...
| Main Authors: | , , , , , , , , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
BMJ Publishing Group
2022-08-01
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| Series: | Journal for ImmunoTherapy of Cancer |
| Online Access: | https://jitc.bmj.com/content/10/8/e005332.full |
| _version_ | 1828148397577601024 |
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| author | Ignacio I Wistuba Andrew Futreal Xuemei Wang Arvind Dasari Cathy Eng Scott Kopetz Edwin R Parra Cara L Haymaker Eduardo Vilar Robert A Wolff Kanwal Raghav Michael J Overman Younghee Lee Benny Johnson Luisa Maren Solis Soto Jane V Thomas Van K Morris Bryan K Kee Christine M Parseghian Daniele Lorenzini Caddie Laberiano-Fernandez Anuj Verma Wenhua Lang |
| author_facet | Ignacio I Wistuba Andrew Futreal Xuemei Wang Arvind Dasari Cathy Eng Scott Kopetz Edwin R Parra Cara L Haymaker Eduardo Vilar Robert A Wolff Kanwal Raghav Michael J Overman Younghee Lee Benny Johnson Luisa Maren Solis Soto Jane V Thomas Van K Morris Bryan K Kee Christine M Parseghian Daniele Lorenzini Caddie Laberiano-Fernandez Anuj Verma Wenhua Lang |
| author_sort | Ignacio I Wistuba |
| collection | DOAJ |
| description | Background Monotherapy with immune checkpoint blockade is ineffective for patients (pts) with microsatellite stable (MSS) metastatic colorectal cancer (mCRC). This study investigates whether the combination of trametinib (T) with durvalumab (D) can alter the immune tumor microenvironment (TME) by successfully priming and activating T-cells.Methods Open-label, single-center, phase II trial with primary endpoint of immune-related response rate for combination of T+D in refractory MSS mCRC pts (NCT03428126). T is 2 mg/day orally starting 1 week prior to D, which is given 1500 mg intravenously every 4 weeks. Simon 2-stage design used to enroll 29 pts into first stage, requiring a response in two or more pts to proceed to stage 2. Tumor biopsies were collected at baseline (BL) and early on-treatment (OT) at week 4.Results Twenty nine treated pts include 48% females, median age 48 years (range 28–75), and median prior therapies 2 (range 1–5). No grade (G) 4 or 5 treatment-related adverse events (TRAE). The most common TRAE of any grade was acneiform rash, 17% being G3. One of 29 pts had confirmed partial response (PR) lasting 9.3 months (mo) for an overall response rate of 3.4%. Seven pts had stable disease (SD) and five pts (1 PR, 4 SD) demonstrated decrease in total carcinoembryonic antigen ng/mL (best percentage reduction: 94%, 95%, 42%, 34%, and 22%, respectively). Median progression-free survival was 3.2 mo (range 1.1–9.3 months). Three pts with both liver and lung metastases demonstrated discrepant responses in which clinical benefit was present in the lung metastases but not liver metastases. Comparison of BL and 4-week OT tumor tissue flow cytometry demonstrated no changes in T-cell infiltration but upregulation expression of PD-1 and Tim3 on CD8 T cells. However, expression of PD-1 and Tim3 as single markers and as coexpressed markers was observed to increase OT relative to BL (p=0.03, p=0.06 and p=0.06, respectively).Conclusions T+D demonstrated acceptable tolerability in pts with refractory MSS mCRC. The response rate in the first stage of the study did not meet efficacy criteria to proceed to the second stage. Specific site of metastatic disease may impact outcomes in novel immunotherapy combination trials.Trial registration number NCT03428126. |
| first_indexed | 2024-04-11T21:14:18Z |
| format | Article |
| id | doaj.art-df046ec2d0ff48c99275fc303b6ac56b |
| institution | Directory Open Access Journal |
| issn | 2051-1426 |
| language | English |
| last_indexed | 2024-04-11T21:14:18Z |
| publishDate | 2022-08-01 |
| publisher | BMJ Publishing Group |
| record_format | Article |
| series | Journal for ImmunoTherapy of Cancer |
| spelling | doaj.art-df046ec2d0ff48c99275fc303b6ac56b2022-12-22T04:02:52ZengBMJ Publishing GroupJournal for ImmunoTherapy of Cancer2051-14262022-08-0110810.1136/jitc-2022-005332Phase II study of durvalumab (anti-PD-L1) and trametinib (MEKi) in microsatellite stable (MSS) metastatic colorectal cancer (mCRC)Ignacio I Wistuba0Andrew Futreal1Xuemei Wang2Arvind Dasari3Cathy Eng4Scott Kopetz5Edwin R Parra6Cara L Haymaker7Eduardo Vilar8Robert A Wolff9Kanwal Raghav10Michael J Overman11Younghee Lee12Benny Johnson13Luisa Maren Solis Soto14Jane V Thomas15Van K Morris16Bryan K Kee17Christine M Parseghian18Daniele Lorenzini19Caddie Laberiano-Fernandez20Anuj Verma21Wenhua Lang228 Department of Translational Molecular Pathology, University of Texas MD Anderson Cancer Center, Houston, Texas, USAAff1 grid.240145.60000000122914776The University of Texas MD Anderson Cancer Center Houston TX USADepartment of Biostatistics, The University of Texas MD Anderson Cancer Center, Houston, Texas, USAAff4 0000 0001 2291 4776grid.240145.6MD Anderson Cancer Center Houston USADepartment of Medicine, Division of Hematology/Oncology, Vanderbilt University Medical Center, Nashville, Tennessee, USAGI Medical Oncology, University of Texas MD Anderson Cancer Center, Houston, Texas, USADepartment of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USADepartment of Translational Molecular Pathology, University of Texas MD Anderson Cancer Center, Houston, Texas, USAMD Anderson Cancer Center UTHealth Graduate School of Biomedical Sciences, University of Texas MD Anderson Cancer Center, Houston, Texas, USADepartment of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USADepartment of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USADepartment of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USAThe University of Texas MD Anderson Cancer Center, Houston, TX, United StatesDepartment of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USADepartment of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USADepartment of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USADepartment of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USADepartment of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USADepartment of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USADepartment of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USADepartment of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USADepartment of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USADepartment of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USABackground Monotherapy with immune checkpoint blockade is ineffective for patients (pts) with microsatellite stable (MSS) metastatic colorectal cancer (mCRC). This study investigates whether the combination of trametinib (T) with durvalumab (D) can alter the immune tumor microenvironment (TME) by successfully priming and activating T-cells.Methods Open-label, single-center, phase II trial with primary endpoint of immune-related response rate for combination of T+D in refractory MSS mCRC pts (NCT03428126). T is 2 mg/day orally starting 1 week prior to D, which is given 1500 mg intravenously every 4 weeks. Simon 2-stage design used to enroll 29 pts into first stage, requiring a response in two or more pts to proceed to stage 2. Tumor biopsies were collected at baseline (BL) and early on-treatment (OT) at week 4.Results Twenty nine treated pts include 48% females, median age 48 years (range 28–75), and median prior therapies 2 (range 1–5). No grade (G) 4 or 5 treatment-related adverse events (TRAE). The most common TRAE of any grade was acneiform rash, 17% being G3. One of 29 pts had confirmed partial response (PR) lasting 9.3 months (mo) for an overall response rate of 3.4%. Seven pts had stable disease (SD) and five pts (1 PR, 4 SD) demonstrated decrease in total carcinoembryonic antigen ng/mL (best percentage reduction: 94%, 95%, 42%, 34%, and 22%, respectively). Median progression-free survival was 3.2 mo (range 1.1–9.3 months). Three pts with both liver and lung metastases demonstrated discrepant responses in which clinical benefit was present in the lung metastases but not liver metastases. Comparison of BL and 4-week OT tumor tissue flow cytometry demonstrated no changes in T-cell infiltration but upregulation expression of PD-1 and Tim3 on CD8 T cells. However, expression of PD-1 and Tim3 as single markers and as coexpressed markers was observed to increase OT relative to BL (p=0.03, p=0.06 and p=0.06, respectively).Conclusions T+D demonstrated acceptable tolerability in pts with refractory MSS mCRC. The response rate in the first stage of the study did not meet efficacy criteria to proceed to the second stage. Specific site of metastatic disease may impact outcomes in novel immunotherapy combination trials.Trial registration number NCT03428126.https://jitc.bmj.com/content/10/8/e005332.full |
| spellingShingle | Ignacio I Wistuba Andrew Futreal Xuemei Wang Arvind Dasari Cathy Eng Scott Kopetz Edwin R Parra Cara L Haymaker Eduardo Vilar Robert A Wolff Kanwal Raghav Michael J Overman Younghee Lee Benny Johnson Luisa Maren Solis Soto Jane V Thomas Van K Morris Bryan K Kee Christine M Parseghian Daniele Lorenzini Caddie Laberiano-Fernandez Anuj Verma Wenhua Lang Phase II study of durvalumab (anti-PD-L1) and trametinib (MEKi) in microsatellite stable (MSS) metastatic colorectal cancer (mCRC) Journal for ImmunoTherapy of Cancer |
| title | Phase II study of durvalumab (anti-PD-L1) and trametinib (MEKi) in microsatellite stable (MSS) metastatic colorectal cancer (mCRC) |
| title_full | Phase II study of durvalumab (anti-PD-L1) and trametinib (MEKi) in microsatellite stable (MSS) metastatic colorectal cancer (mCRC) |
| title_fullStr | Phase II study of durvalumab (anti-PD-L1) and trametinib (MEKi) in microsatellite stable (MSS) metastatic colorectal cancer (mCRC) |
| title_full_unstemmed | Phase II study of durvalumab (anti-PD-L1) and trametinib (MEKi) in microsatellite stable (MSS) metastatic colorectal cancer (mCRC) |
| title_short | Phase II study of durvalumab (anti-PD-L1) and trametinib (MEKi) in microsatellite stable (MSS) metastatic colorectal cancer (mCRC) |
| title_sort | phase ii study of durvalumab anti pd l1 and trametinib meki in microsatellite stable mss metastatic colorectal cancer mcrc |
| url | https://jitc.bmj.com/content/10/8/e005332.full |
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