Phase Ib evaluation of a self-adjuvanted protamine formulated mRNA-based active cancer immunotherapy, BI1361849 (CV9202), combined with local radiation treatment in patients with stage IV non-small cell lung cancer

Abstract

Background: Preclinical studies demonstrate synergism between cancer immunotherapy and local radiation, enhancing anti-tumor effects and promoting immune responses. BI1361849 (CV9202) is an active cancer immunotherapeutic comprising protamine-formulated, sequence-optimized mRNA encoding six non-small cell lung cancer (NSCLC)-associated antigens (NY-ESO-1, MAGE-C1, MAGE-C2, survivin, 5T4, and MUC-1), intended to induce targeted immune responses.

Methods: We describe a phase Ib clinical trial evaluating treatment with BI1361849 combined with local radiation in 26 stage IV NSCLC patients with partial response (PR)/stable disease (SD) after standard first-line therapy. Patients were stratified into three strata (1: non-squamous NSCLC, no epidermal growth factor receptor (EGFR) mutation, PR/SD after ≥4 cycles of platinum- and pemetrexed-based treatment [n = 16]; 2: squamous NSCLC, PR/SD after ≥4 cycles of platinum-based and non-platinum compound treatment [n = 8]; 3: non-squamous NSCLC, EGFR mutation, PR/SD after ≥3 and ≤ 6 months EGFR-tyrosine kinase inhibitor (TKI) treatment [n = 2]). Patients received intradermal BI1361849, local radiation (4 × 5 Gy), then BI1361849 until disease progression. Strata 1 and 3 also had maintenance pemetrexed or continued EGFR-TKI therapy, respectively. The primary endpoint was evaluation of safety; secondary objectives included assessment of clinical efficacy (every 6 weeks during treatment) and of immune response (on Days 1 [baseline], 19 and 61).

Results: Study treatment was well tolerated; injection site reactions and flu-like symptoms were the most common BI1361849-related adverse events. Three patients had grade 3 BI1361849-related adverse events (fatigue, pyrexia); there was one grade 3 radiation-related event (dysphagia). In comparison to baseline, immunomonitoring revealed increased BI1361849 antigen-specific immune responses in the majority of patients (84%), whereby antigen-specific antibody levels were increased in 80% and functional T cells in 40% of patients, and involvement of multiple antigen specificities was evident in 52% of patients. One patient had a partial response in combination with pemetrexed maintenance, and 46.2% achieved stable disease as best overall response. Best overall response was SD in 57.7% for target lesions.

Conclusion: The results support further investigation of mRNA-based immunotherapy in NSCLC including combinations with immune checkpoint inhibitors.

Trial registration: ClinicalTrials.gov identifier: NCT01915524 .

Keywords: BI1361849; CV9202; Clinical trial; Hypofractionated radiotherapy; Immunomonitoring; Non-small cell lung cancer; mRNA active cancer immunotherapy.

Fig. 1

a Study design. b Patient disposition

Fig. 2

Frequencies of patients with an at least two-fold increase in antigen-specific immune responses following BI1361849 immunotherapy combined with local radiation treatment. Values displayed above the bars indicate the percentages and actual number of patients with increase in immune responses. a Summary graph showing frequencies of patients with antigen-specific T cells, antibodies or both exhibiting an at least two-fold increase compared to baseline against one or more antigens encoded by BI1361849 (any post-vaccine time point). CD4 = antigen-specific CD4⁺ T cells, CD8 = antigen-specific CD8⁺ T cells. b Frequencies of patients with an at least a two-fold increase in immune responses compared to baseline to each of the antigens encoded by BI1361849 shown as percentage of all evaluable patients; any post-vaccine time point. c Frequencies of patients with antigen-specific T cells, antibodies or both showing at least a two-fold increase compared to baseline against multiple antigens encoded by BI1361849 shown as percentage of all evaluable patients; at any post-vaccine time point

Fig. 3

a Vaccine antigen-specific CD4⁺ and CD8⁺ T cells detected by ICS at baseline (n = 7 patients for panel CD4, n = 11 patients for panel CD8, n = 16 patients for panel CD4 and/or CD8), and days 19 (n = 13 patients for panel CD4, n = 15 patients for panel CD8, n = 23 patients for panel CD4 and/or CD8) and 61 (n = 7 patients for panel CD4, n = 7 patients for panel CD8, n = 10 patients for panel CD4 and/or CD8) following BI1361849 immunotherapy combined with local radiation treatment. Vaccine antigen-specific T cell responses were determined and are shown as percentages of all possible responses. The denominator for calculating the percentage was defined as the maximum of all possible at least two-fold increases over background (unstimulated cells). Example: 4 functions (IFN-γ, TNF-α, IL-2, CD107a) * 2 T cell subsets (CD4⁺ or CD8⁺ T cells) * 6 BI1361849 antigens * 25 patients = 1200 possible responses. The numbers in the key show fold-increases over the background control. b & c Magnitude of T cell responses as measured by b ICS or c IFN-γ ELISpot of patients with an at least two-fold increase in antigen-specific immune responses following BI1361849 treatment. Values are shown as the percentage of positive cells gated on both CD4⁺ or CD8⁺ populations for ICS. ELISpot results are plotted as number of spots per 1 million PBMCs after background subtraction (PBMCs that received only cell culture medium). Legends indicate patient ID, antigen, measured cytokine (only for ICS) and time point

Fig. 4

Efficacy outcomes following BI1361849 immunotherapy combined with local radiation treatment. a Change in target lesion sum of longest diameters (SLD) from baseline. b Survival, progression-free survival, and response kinetics of individual patients (post hoc swimmer plot)