ONCOS-102 plus pemetrexed and platinum chemotherapy in malignant pleural mesothelioma: a randomized phase 2 study investigating clinical outcomes and the tumor microenvironment

Abstract

Background: ONCOS-102, an oncolytic adenovirus expressing granulocyte-macrophage colony-stimulating factor, can alter the tumor microenvironment to an immunostimulatory state. Combining ONCOS-102 with standard-of-care chemotherapy for malignant pleural mesothelioma (MPM) may improve treatment outcomes.

Methods: In this open-label, randomized study, patients with unresectable MPM received intratumoral ONCOS-102 (3×10¹¹ virus particles on days 1, 4, 8, 36, 78, and 120) and pemetrexed plus cisplatin/carboplatin (from day 22), or pemetrexed plus cisplatin/carboplatin alone. The primary endpoint was safety. Overall survival (OS), progression-free survival, objective response rate, and tumor immunologic activation (baseline and day 36 biopsies) were also assessed.

Results: In total, 31 patients (safety lead-in: n=6, randomized: n=25) were enrolled. Anemia (15.0% and 27.3%) and neutropenia (40.0% and 45.5%) were the most frequent grade ≥3 adverse events (AEs) in the ONCOS-102 (n=20) and chemotherapy-alone (n=11) cohorts. No patients discontinued ONCOS-102 due to AEs. No statistically significant difference in efficacy endpoints was observed. There was a numerical improvement in OS (30-month OS rate 34.1% vs 0; median OS 20.3 vs 13.5 months) with ONCOS-102 versus chemotherapy alone in chemotherapy-naïve patients (n=17). By day 36, ONCOS-102 was associated with increased T-cell infiltration and immune-related gene expression that was not observed in the control cohort. Substantial immune activation in the tumor microenvironment was associated with survival at month 18 in the ONCOS-102 cohort.

Conclusions: ONCOS-102 plus pemetrexed and cisplatin/carboplatin was well tolerated by patients with MPM. In injected tumors, ONCOS-102 promoted a proinflammatory environment, including T-cell infiltration, which showed association with survival at month 18.

Keywords: T-lymphocytes; immunomodulation; oncolytic viruses; therapies, investigational; tumor microenvironment.

Figure 1

Study design. ^aStratified by prior chemotherapy (naïve/non-naïve). ^bCPO 300 mg/m² was administered 1–3 days prior to ONCOS-102 (days −3 to −1 and days 75 to 77). ^cSix intratumoral injections (days 1, 4, 8, 36, 78, 120) containing 3×10¹¹ virus particles in 2.5 mL across 1–5 lesions (≥0.5 mL/lesion). ^dPemetrexed (500 mg/m²) with cisplatin (75 mg/m²) or carboplatin (AUC 5, following a protocol amendment) administered in 21-day cycles starting on day 22 for up to six cycles, along with folic acid, vitamin B₁₂, and dexamethasone in accordance with local practices. Blood samples for cytokine and other analyses were obtained prior to study medication on days 1, 43, 85, and 127 in the chemotherapy-alone cohort and on days 1, 4, 8, 36, 78, and 120 in the ONCOS-102 randomized cohort, and at predose and postdose in the phase Ib safety lead-in cohort. Imaging time points are shown for ONCOS-102 cohort. Tumor imaging was performed at baseline, weeks 6 and 18 in the control group. AUC, area under the concentration–time curve; BL, baseline, CPO, cyclophosphamide.

Figure 2

Patient disposition. ^aAllocated to ONCOS-102 (3×10¹¹ virus particles in 2.5 mL) with pemetrexed (500 mg/m²) in combination with cisplatin (75 mg/m²) or carboplatin (AUC 5) in 21-day cycles. ^bRandomized to pemetrexed (500 mg/m²) in combination with cisplatin (75 mg/m²) or carboplatin (AUC 5) in 21-day cycles. ^cData were pooled from safety cohort and ONCOS-102 randomized cohort. ^dAs all enrolled patients received study treatment, the ITT population was used to summarize efficacy and safety outcomes. AUC, area under the concentration–time curve; ITT, intention to treat.

Figure 3

Overall survival and progression-free survival (ITT population). Kaplan-Meier probability curves of OS (A, C) and PFS (B, D) in relation to treatment regimen for the pooled population (n=31) and chemotherapy-naïve subgroup (n=17). Censored values (+) indicate the last follow-up time for patients who were alive after study completion. P values were obtained by log-rank tests. Control is pemetrexed (500 mg/m²) in combination with cisplatin (75 mg/m²) or carboplatin (AUC 5). ONCOS-102 is ONCOS-102 (3×10¹¹ virus particles in 2.5 mL) with pemetrexed (500 mg/m²) in combination with cisplatin (75 mg/m²) or carboplatin (AUC 5). ITT, intention to treat; NA, not assessable; PFS, progression-free survival; OS, overall survival.

Figure 4

Change in tumor immune cell profile over time. Immunofluorescence histology for CD4+ (A), CD8+ (B), GranzymeB-positive CD8+ cells (C), CD8+:Treg ratio (D), and M1:M2 (E) for the chemotherapy-alone (left panel) and ONCOS-102 (right panel) groups at baseline and day 36. Boxes show median, lower, and upper quartiles, whiskers show minimum and maximum values within the 1.5 IQR, individual points denote outliers, and values in parentheses denote patients with available samples. P values are derived from quasi-binomial generalized linear model (A–C) or linear regression (D, E). (F) Change in gene expression in select immunological pathways (specified in online supplemental data) from day 36 relative to baseline, stratified by study treatment (number of genes in each pathway are denoted in parentheses). (G) Normalized (using DESeq2) expression of T-cell marker genes at baseline and day 36 stratified by study treatment (values in parentheses denote patients with available samples). (H) Deconvolution of cell-type abundance from transcriptome expression profiles for patients in the chemotherapy-alone (left panel) and ONCOS-102 (right panel) cohorts at baseline and day 36 (colors reflects subsets of CD4+ and CD8+ T-cells). Control is pemetrexed (500 mg/m²) in combination with cisplatin (75 mg/m²) or carboplatin (AUC 5). ONCOS-102 is ONCOS-102 (3×10¹¹ virus particles in 2.5 mL) with pemetrexed (500 mg/m²) in combination with cisplatin (75 mg/m²) or carboplatin (AUC 5). *p≤0.05; **p≤0.01. AUC, area under the concentration–time curve; BL, baseline; D, study day, GM-CSF, granulocyte-macrophage colony stimulating factor; IQR, interquartile range; M, macrophage; T_CM, central memory T-cells; T_EM, effector memory T-cells; TLR9, toll-like receptor 9; Treg, regulatory T-cells.

Figure 5

Tumor immune cell profile and gene expression, stratified by survival at 18 months (ONCOS-102 group^a). Immunofluorescence histology for CD4+ (A), CD8+ (B), GranzymeB-positive CD8+ cells (C), CD8+:Treg ratio(D), and M1:M2 (E) at baseline and day 36 for patients treated with ONCOS-102 who survived (left panel) and had died (right panel) at month 18. Boxes show median, lower, and upper quartiles, whiskers show minimum and maximum values within the 1.5 IQR, individual data points are shown, and values in parentheses denote number of patients with available samples. P values are derived from quasi-binomial generalized linear model (A–C) or linear regression (D, E). (F) Change in gene expression in select immunological pathways (specified in online supplemental data) from day 36 relative to baseline, stratified by survival at month 18 (number of genes in each pathway are denoted in parentheses). (G) Normalized (using DESeq2) expression of T-cell marker genes at baseline and day 36 stratified by survival at month 18 (values in parentheses denote patients with available samples). (H) Deconvolution of cell-type abundance from transcriptome expression profiles for patients at baseline and day 36 (colors reflect subsets of CD4+ and CD8+ T-cells) who were alive (left panel) and decreased (right panel) at month 18. (I) Serum GM-CSF levels at baseline and days 4, 8, 36, 78, and 120, stratified by 18-month survival. ^aONCOS-102 (3×10¹¹ virus particles in 2.5 mL) with pemetrexed (500 mg/m²) in combination with cisplatin (75 mg/m²) or carboplatin (AUC 5). *p≤0.05; **p≤0.01. AUC, area under the concentration–time curve; BL, baseline; D, study day, GM-CSF, granulocyte-macrophage colony-stimulating factor; IQR, interquartile range; M, macrophage; T_CM, central memory T-cells; T_EM, effector memory T-cells; TLR9, toll-like receptor 9; Treg, regulatory T-cells.