Anti-CSF-1R emactuzumab in combination with anti-PD-L1 atezolizumab in advanced solid tumor patients naïve or experienced for immune checkpoint blockade

Abstract

Background: This phase 1b study (NCT02323191) evaluated the safety, antitumor activity, pharmacokinetics, and pharmacodynamics of colony-stimulating factor-1 receptor-blocking monoclonal antibody (mAb) emactuzumab in combination with the programmed cell death-1 ligand (PD-L1)-blocking mAb atezolizumab in patients with advanced solid tumors naïve or experienced for immune checkpoint blockers (ICBs).

Methods: Emactuzumab (500-1350 mg flat) and atezolizumab (1200 mg flat) were administered intravenously every 3 weeks. Dose escalation of emactuzumab was conducted using the 3+3 design up to the maximum tolerated dose (MTD) or optimal biological dose (OBD). Extension cohorts to evaluate pharmacodynamics and clinical activity were conducted in metastatic ICB-naive urothelial bladder cancer (UBC) and ICB-pretreated melanoma (MEL), non-small cell lung cancer (NSCLC) and UBC patients.

Results: Overall, 221 patients were treated. No MTD was reached and the OBD was determined at 1000 mg of emactuzumab in combination with 1200 mg of atezolizumab. Grade ≥3 treatment-related adverse events occurred in 25 (11.3%) patients of which fatigue and rash were the most common (14 patients (6.3%) each). The confirmed objective response rate (ORR) was 9.8% for ICB-naïve UBC, 12.5% for ICB-experienced NSCLC, 8.3% for ICB-experienced UBC and 5.6% for ICB-experienced MEL patients, respectively. Tumor biopsy analyses demonstrated increased activated CD8 +tumor infiltrating T lymphocytes (TILs) associated with clinical benefit in ICB-naïve UBC patients and less tumor-associated macrophage (TAM) reduction in ICB-experienced compared with ICB-naïve patients.

Conclusion: Emactuzumab in combination with atezolizumab demonstrated a manageable safety profile with increased fatigue and skin rash over usual atezolizumab monotherapy. A considerable ORR was particularly seen in ICB-experienced NSCLC patients. Increase ofCD8 +TILs under therapy appeared to be associated with persistence of a TAM subpopulation.

Keywords: Clinical Trials as Topic; Drug Therapy, Combination; Immunotherapy; Macrophages; T-Lymphocytes.

Figure 1

Flow diagram of study design, patient enrolment and emactuzumab dose. All patients received 1200 mg of atezolizumab in combination with emactuzumab q3w. AE, adverse event; GC, gastric cancer; MEL, melanoma; n, number of patients; NSCLC, non-small cell lung cancer; OvCa, ovarian carcinoma; PD, progressive disease; STS, soft tissue sarcoma; TNBC, triple-negative breast cancer; UBC, urothelial bladder cancer cancer.

Figure 2

Waterfall plot based on RECIST criteria per investigator assessment (A) ICB-naïve UBC patients (B) ICB-experienced melanoma patients (C) ICB-experienced NSCLC patients (D) ICB-experienced UBC patients. ICB, immune checkpoint blocker; NSCLC, non-small cell lung cancer; UBC, urothelial bladder cancer.

Figure 3

Change from baseline of tumor-associated macrophages and tumor-infiltrating T cells in paired biopsies and comparison of progressive disease patients versus non-progressive disease patients in the UBC ICB-naïve cohort. Clinical responses are indicated. CR, complete response; ICB, immune checkpoint blocker; PD, progressive disease; PR, partial response; SD, stable disease; UBC, urothelial bladder cancer.

Figure 4

Baseline comparison of tumor-associated macrophages and tumor-infiltrating T cells and comparison of progressive disease (PD) patients versus non-PD patients in the ICB-naïve UBC and in the ICB-experienced UBC, NSCLC and MEL cohort. Clinical responses are indicated. ICB, immune checkpoint blocker; MEL, melanoma; NSCLC, non-small cell lung cancer; PR, partial response; SD, stable disease; UBC, urothelial bladder cancer.