Phase 1/2 study of monalizumab plus durvalumab in patients with advanced solid tumors.

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

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.

Informations de copyright

© 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.

Déclaration de conflit d'intérêts

Competing interests: SP: scientific advisory income from: Amgen, AstraZeneca, Bristol Myers Squibb, Certis, Eli Lilly, Genentech, Illumina, Merck, Pfizer, Rakuten, and Tempus; SP’s university receives research funding from: Amgen, AstraZeneca/MedImmune, Bristol Myers Squibb, Eli Lilly, Fate Therapeutics, Iovance, Merck, Pfizer, Roche/Genentech, and SQZ Biotechnologies.TA-G has received research funding, honoraria, and non-financial or other support from IPSEN, Adacap, Pfizer, Sanofi, EISAI, Lilly, Bayer, Janssen, BMS, Astellas, Novartis, Roche, and Merck. SB: institutional grants: AstraZeneca and GlaxoSmithKline. Honoraria for Advisory boards: Amgen, AstraZeneca, Genmab, GlaxoSmithKline, Immunogen, Merck Sharp & Dohme, Merck Sereno, Mersana Therapeutics, OncXerna, Seagen, and Shattuck Labs; Honoraria for lectures: Amgen, AstraZeneca, Clovis, GlaxoSmithKline, Immunogen, Merck Sharp & Dohme, Mersana Therapeutics, Pfizer, and Roche. DW, JN, NES, DCP, L-YC, PK, MDH: employment by and stock ownership/options in AstraZeneca. MLA: former employment by and stock ownership/options in AstraZeneca. MD: employment by and stock ownership/options in AstraZeneca. JRD: institutional funds received from: AstraZeneca, Abbvie, Astellas, Gilead, Merck, Deciphera, Hutchison, BMS, Adlai Norte, Takeda, OnKure Therapeutics; Consulting: Gilead, OnKure Therapeutics; Equity Interest: OnKure Therapeutics. BAC: institutional research support: Astra Zeneca, Abbvie, Actuate Therapeutics, Astellas, Bayer, Dragonfly Therapeutics, Pfizer, Repare Therapeutics. Scientific advisory boards: Foundation Medicine, Tempus, Seattle Genetics, G1 therapeutics.