A Phase II Window of Opportunity Study of Neoadjuvant PD-L1 versus PD-L1 plus CTLA-4 Blockade for Patients with Malignant Pleural Mesothelioma

Authors

Hyun-Sung Lee
Hee-Jin Jang
Maheshwari Ramineni
Daniel Y Wang
Daniela Ramos
Jong Min Choi
Taylor Splawn
Monica Espinoza
Michelle Almarez
Leandria Hosey
Eunji Jo
Susan Hilsenbeck
Christopher I Amos
R Taylor Ripley
Bryan M Burt

Publication Date

2-1-2023

Journal

Clinical Cancer Research

DOI

10.1158/1078-0432.CCR-22-2566

PMID

36469573

PMCID

PMC9898180

PubMedCentral® Posted Date

2-1-2024

PubMedCentral® Full Text Version

Author MSS

Published Open-Access

yes

Keywords

Humans, B7-H1 Antigen, CTLA-4 Antigen, Lung Neoplasms, Mesothelioma, Mesothelioma, Malignant, Neoadjuvant Therapy, Pleural Neoplasms, Tumor Microenvironment

Abstract

Purpose: We report the results of a phase II, randomized, window-of-opportunity trial of neoadjuvant durvalumab versus durvalumab plus tremelimumab followed by surgery in patients with resectable malignant pleural mesothelioma (MPM; NCT02592551).

Patients and methods: The primary objective was alteration of the intratumoral CD8/regulatory T cell (Treg) ratio after combination immune checkpoint blockade (ICB) therapy. Secondary and exploratory objectives included other changes in the tumor microenvironment, survival, safety, tumor pathologic response (PR), and systemic immune responses.

Results: Nine patients received monotherapy and 11 received combination therapy. Seventeen of the 20 patients (85%) receiving ICB underwent planned thoracotomy. Both ICB regimens induced CD8 T-cell infiltration into MPM tumors but did not alter CD8/Treg ratios. At 34.1 months follow-up, patients receiving combination ICB had longer median overall survival (not reached) compared with those receiving monotherapy (14.0 months). Grade ≥3 immunotoxicity occurred in 8% of patients in the monotherapy group and 27% of patients in the combination group. Tumor PR occurred in 6 of 17 patients receiving ICB and thoracotomy (35.3%), among which major PR (>90% tumor regression) occurred in 2 (11.8%). Single-cell profiling of tumor, blood, and bone marrow revealed that combination ICB remodeled the immune contexture of MPM tumors; mobilized CD57+ effector memory T cells from the bone marrow to the circulation; and increased the formation of tertiary lymphoid structures in MPM tumors that were rich in CD57+ T cells.

Conclusions: These data indicate that neoadjuvant durvalumab plus tremelimumab orchestrates de novo systemic immune responses that extend to the tumor microenvironment and correlate with favorable clinical outcomes.