| Abstract: |
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. © 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. |
| Keywords: |
adolescent; adult; controlled study; human tissue; aged; major clinical study; overall survival; clinical trial; constipation; drug tolerability; fatigue; diarrhea; drug efficacy; drug safety; solid tumor; cancer staging; outcome assessment; follow up; cancer grading; endometrium cancer; colorectal cancer; cd8+ t lymphocyte; cell proliferation; t lymphocyte; cancer immunotherapy; progression free survival; ovary cancer; pharmacodynamics; phase 2 clinical trial; anemia; cell infiltration; tumor volume; nausea; vomiting; carcinoma, non-small-cell lung; lung neoplasms; myalgia; clinical assessment; cohort analysis; tumor biopsy; antineoplastic activity; histology; hematuria; monoclonal antibody; alanine aminotransferase blood level; arthralgia; asthenia; dyspnea; fever; hyperuricemia; hypomagnesemia; pneumonia; pruritus; lung embolism; lung tumor; acute kidney failure; hypermagnesemia; hypokalemia; hyponatremia; granzyme b; antibodies, monoclonal; multicenter study; mismatch repair; microsatellite instability; uterine cervix cancer; urinary tract infection; ligand; creatine; ligands; pancreas adenocarcinoma; natural killer cell; tumor immunity; colitis; innate immunity; immunity, innate; maximum tolerated dose; phase 1 clinical trial; drug dose increase; adaptive immunity; gamma interferon inducible protein 10; abnormally high substrate concentration in blood; hematoma; anaphylaxis; cell activation; pericarditis; hypocalcemia; hydronephrosis; castration resistant prostate cancer; non small cell lung cancer; tumor microenvironment; decreased appetite; natural killer t-cells; pyelonephritis; autoimmune encephalitis; encephalomyelitis; nephritis; myocarditis; cxcl11 chemokine; response evaluation criteria in solid tumors; antibodies, monoclonal, humanized; infusion related reaction; humans; human; male; female; article; programmed cell death 1 receptor; durvalumab; ecog performance status; monalizumab; hyperlipasemia; subcapsular renal hematoma
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