Phase 1/2 study of monalizumab plus durvalumab in patients with advanced solid tumors
© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ..
BACKGROUND: The combination of monalizumab (anti-NKG2A/CD94) and durvalumab (anti-programmed death ligand-1) may promote antitumor immunity by targeting innate and adaptive immunity. This phase 1/2 study of monalizumab and durvalumab evaluated safety, antitumor activity, and pharmacodynamics in patients with advanced solid tumors.
MAIN BODY: Immunotherapy-naïve patients aged ≥18 years with advanced disease, Eastern Cooperative Oncology Group performance status of 0-1, and 1-3 prior lines of systemic therapy in the recurrent/metastatic setting were enrolled. In part 1 (dose escalation), patients received durvalumab 1500 mg every 4 weeks (Q4W) with increasing doses of monalizumab Q2W/Q4W (n=15). Dose expansion in part 1 included patients with cervical cancer (n=15; durvalumab 1500 mg Q4W and monalizumab 750 mg Q2W) or metastatic microsatellite stable (MSS)-colorectal cancer (CRC) (n=15; durvalumab 1500 mg Q4W and monalizumab 750 mg Q4W). In part 2 (dose expansion), patients with MSS-CRC (n=40), non-small cell lung cancer (NSCLC; n=20), MSS-endometrial cancer (n=40), or ovarian cancer (n=40) received durvalumab 1500 mg Q4W and monalizumab 750 mg Q2W. The primary endpoint was safety. Secondary endpoints included antitumor activity per Response Evaluation Criteria In Solid Tumors version 1.1 (RECIST v1.1). Exploratory analyses included assessment of T-cell and natural killer (NK) cell activation and proliferation in peripheral blood and the tumor microenvironment (TME). The study enrolled 185 patients (part 1, 45; part 2, 140). No dose-limiting toxicities were observed and the maximum tolerated dose was not reached. In part 2, the most common treatment-related adverse events were fatigue (12.1%), asthenia (9.3%), diarrhea (9.3%), pruritus (7.9%), and pyrexia (7.1%). In the expansion cohorts, response rates were 0% (cervical), 7.7% (MSS-CRC), 10% (NSCLC), 5.4% (ovarian), and 0% (MSS-endometrial). Sustained NK cell activation, CD8+ T-cell proliferation, increased serum levels of CXCL10 (C-X-C motif chemokine ligand 10) and CXCL11, and increased tumor infiltration of CD8+ and granzyme B+ cells were observed.
CONCLUSIONS: Although efficacy was modest, monalizumab plus durvalumab was well tolerated and encouraging immune activation was observed in the peripheral blood and TME.
TRIAL REGISTRATION NUMBER: NCT02671435.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2024 |
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| Erschienen: |
2024 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:12 |
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| Enthalten in: |
Journal for immunotherapy of cancer - 12(2024), 2 vom: 02. Feb. |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Patel, Sandip P [VerfasserIn] |
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| Links: |
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| Anmerkungen: |
Date Completed 05.02.2024 Date Revised 13.04.2024 published: Electronic ClinicalTrials.gov: NCT02671435 Citation Status MEDLINE |
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| doi: |
10.1136/jitc-2023-007340 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| PPN (Katalog-ID): |
NLM367992051 |
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| 100 | 1 | |a Patel, Sandip P |e verfasserin |4 aut | |
| 245 | 1 | 0 | |a Phase 1/2 study of monalizumab plus durvalumab in patients with advanced solid tumors |
| 264 | 1 | |c 2024 | |
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| 500 | |a Date Revised 13.04.2024 | ||
| 500 | |a published: Electronic | ||
| 500 | |a ClinicalTrials.gov: NCT02671435 | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a © Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ. | ||
| 520 | |a BACKGROUND: The combination of monalizumab (anti-NKG2A/CD94) and durvalumab (anti-programmed death ligand-1) may promote antitumor immunity by targeting innate and adaptive immunity. This phase 1/2 study of monalizumab and durvalumab evaluated safety, antitumor activity, and pharmacodynamics in patients with advanced solid tumors | ||
| 520 | |a MAIN BODY: Immunotherapy-naïve patients aged ≥18 years with advanced disease, Eastern Cooperative Oncology Group performance status of 0-1, and 1-3 prior lines of systemic therapy in the recurrent/metastatic setting were enrolled. In part 1 (dose escalation), patients received durvalumab 1500 mg every 4 weeks (Q4W) with increasing doses of monalizumab Q2W/Q4W (n=15). Dose expansion in part 1 included patients with cervical cancer (n=15; durvalumab 1500 mg Q4W and monalizumab 750 mg Q2W) or metastatic microsatellite stable (MSS)-colorectal cancer (CRC) (n=15; durvalumab 1500 mg Q4W and monalizumab 750 mg Q4W). In part 2 (dose expansion), patients with MSS-CRC (n=40), non-small cell lung cancer (NSCLC; n=20), MSS-endometrial cancer (n=40), or ovarian cancer (n=40) received durvalumab 1500 mg Q4W and monalizumab 750 mg Q2W. The primary endpoint was safety. Secondary endpoints included antitumor activity per Response Evaluation Criteria In Solid Tumors version 1.1 (RECIST v1.1). Exploratory analyses included assessment of T-cell and natural killer (NK) cell activation and proliferation in peripheral blood and the tumor microenvironment (TME). The study enrolled 185 patients (part 1, 45; part 2, 140). No dose-limiting toxicities were observed and the maximum tolerated dose was not reached. In part 2, the most common treatment-related adverse events were fatigue (12.1%), asthenia (9.3%), diarrhea (9.3%), pruritus (7.9%), and pyrexia (7.1%). In the expansion cohorts, response rates were 0% (cervical), 7.7% (MSS-CRC), 10% (NSCLC), 5.4% (ovarian), and 0% (MSS-endometrial). Sustained NK cell activation, CD8+ T-cell proliferation, increased serum levels of CXCL10 (C-X-C motif chemokine ligand 10) and CXCL11, and increased tumor infiltration of CD8+ and granzyme B+ cells were observed | ||
| 520 | |a CONCLUSIONS: Although efficacy was modest, monalizumab plus durvalumab was well tolerated and encouraging immune activation was observed in the peripheral blood and TME | ||
| 520 | |a TRIAL REGISTRATION NUMBER: NCT02671435 | ||
| 650 | 4 | |a Clinical Trial, Phase II | |
| 650 | 4 | |a Clinical Trial, Phase I | |
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a Adaptive Immunity | |
| 650 | 4 | |a Immunity, Innate | |
| 650 | 4 | |a Natural Killer T-Cells | |
| 650 | 4 | |a Programmed Cell Death 1 Receptor | |
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| 650 | 7 | |a monalizumab |2 NLM | |
| 650 | 7 | |a 3ZXZ2V0588 |2 NLM | |
| 650 | 7 | |a Ligands |2 NLM | |
| 650 | 7 | |a Antibodies, Monoclonal |2 NLM | |
| 650 | 7 | |a Antibodies, Monoclonal, Humanized |2 NLM | |
| 700 | 1 | |a Alonso-Gordoa, Teresa |e verfasserin |4 aut | |
| 700 | 1 | |a Banerjee, Susana |e verfasserin |4 aut | |
| 700 | 1 | |a Wang, Ding |e verfasserin |4 aut | |
| 700 | 1 | |a Naidoo, Jarushka |e verfasserin |4 aut | |
| 700 | 1 | |a Standifer, Nathan E |e verfasserin |4 aut | |
| 700 | 1 | |a Palmer, Doug C |e verfasserin |4 aut | |
| 700 | 1 | |a Cheng, Lin-Yang |e verfasserin |4 aut | |
| 700 | 1 | |a Kourtesis, Panagiotis |e verfasserin |4 aut | |
| 700 | 1 | |a Ascierto, Maria L |e verfasserin |4 aut | |
| 700 | 1 | |a Das, Mayukh |e verfasserin |4 aut | |
| 700 | 1 | |a Diamond, Jennifer R |e verfasserin |4 aut | |
| 700 | 1 | |a Hellmann, Matthew D |e verfasserin |4 aut | |
| 700 | 1 | |a Carneiro, Benedito A |e verfasserin |4 aut | |
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