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

J Immunother Cancer. 2019 Feb 8;7(1):38. doi: 10.1186/s40425-019-0520-5.


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: identifier: NCT01915524 .

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

Publication types

  • Clinical Trial, Phase I
  • Multicenter Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adjuvants, Immunologic / therapeutic use*
  • Adult
  • Aged
  • Aged, 80 and over
  • Antigens, Neoplasm / genetics
  • Antineoplastic Agents / therapeutic use*
  • Carcinoma, Non-Small-Cell Lung / immunology
  • Carcinoma, Non-Small-Cell Lung / therapy*
  • Combined Modality Therapy
  • Female
  • Humans
  • Immunotherapy*
  • Lung Neoplasms / immunology
  • Lung Neoplasms / radiotherapy*
  • Lung Neoplasms / therapy*
  • Male
  • Membrane Glycoproteins / genetics
  • Membrane Proteins / genetics
  • Middle Aged
  • Mucin-1 / genetics
  • Neoplasm Proteins / genetics
  • Pemetrexed / therapeutic use*
  • Protamines / therapeutic use*
  • RNA, Messenger / therapeutic use*
  • Survivin / genetics


  • Adjuvants, Immunologic
  • Antigens, Neoplasm
  • Antineoplastic Agents
  • BIRC5 protein, human
  • CTAG1B protein, human
  • MAGEC1 protein, human
  • MAGEC2 protein, human
  • MUC1 protein, human
  • Membrane Glycoproteins
  • Membrane Proteins
  • Mucin-1
  • Neoplasm Proteins
  • Protamines
  • RNA, Messenger
  • Survivin
  • trophoblastic glycoprotein 5T4, human
  • Pemetrexed

Associated data