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

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.

Keywords: Adaptive Immunity; Immunity, Innate; Natural Killer T-Cells; Programmed Cell Death 1 Receptor; Tumor Microenvironment.

Figure 1

Change in tumor size from baseline for (A) MSS-CRC, (B) ovarian cancer, (C) MSS-endometrial cancer, (D) NSCLC, and (E) cervical cancer (part 1 and part 2 dose-expansion cohorts; response-evaluable population). (A) In the MSS-CRC cohort, there were 4 out of 37 patients with >30% reduction in sum of target lesions; however, 3 had disease response per RECIST v1.1. (B) In the ovarian cancer cohort, there were 2 out of 35 patients with >30% reduction in sum of target lesions and these 2 patients also had disease response per RECIST v1.1. (C) In the MSS-endometrial cancer cohort, there was 1 out of 35 patients with >30% reduction in sum of target lesions; however, there were no tumor responses per RECIST v1.1. (D) In the NSCLC cohort, there were 3 out of 18 patients with >30% reduction in sum of target lesions; however, 1 patient had disease response per RECIST v1.1. (E) In the cervical cancer cohort, there was 1 out of 15 patients with >30% reduction in sum of target lesions; however, there were no tumor responses per RECIST v1.1. MSS, microsatellite stable; MSS-CRC, microsatellite-stable colorectal cancer; NSCLC, non-small cell lung cancer; RECIST v1.1, Response Evaluation Criteria In Solid Tumors version 1.1.

Figure 2

Change in lymphocyte subpopulations in the circulation before and after treatment with monalizumab and durvalumab (A) Lin3⁻ CD16⁻ CD56⁺ NK, (B) CD38 relative expression on Lin3⁻ CD16⁻ CD56⁺ CD38⁺ NK, and (C) CD3⁺ CD4⁺ Ki67⁺ or CD3⁺ CD8⁺ Ki67⁺ T cells. Samples were from patients in the NSCLC, MSS-CRC, MSS-endometrial cancer, and ovarian cancer expansion cohorts. Error bars represent SE of the mean. Lin3⁻, negative for expression of lineage markers for T and B cells and monocytes (CD3, CD14, CD19, and CD20). *P<0.01 versus change from baseline value on study day −5 using pair-wise comparison by Wilcoxon method. MSS, microsatellite stable; MSS-CRC, microsatellite-stable colorectal cancer; NK, natural killer; NSCLC, non-small cell lung cancer.

Figure 3

Immune activation in the periphery and tumor microenvironment. Levels of immune activating cytokines (A) CXCL10 and (B) CXCL11 at baseline and after monalizumab and durvalumab treatment. Intratumoral levels of (C) CD3⁺Ki67⁺, (D) GZMB, (E) NKp46, and (F) CD8 cells at baseline and after monalizumab and durvalumab treatment. Samples were obtained from patients treated with monalizumab and durvalumab in the NSCLC, CRC, MSS-endometrial cancer, and ovarian cancer expansion cohorts. CXCL-10, C-X-C motif chemokine ligand 10; CXCL11, C-X-C motif chemokine ligand 11; D, day; GZMB, Granzyme B; MSS, microsatellite stable; MSS-CRC, microsatellite-stable colorectal cancer; NSCLC, non-small cell lung cancer; W, week.