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

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.

Author information

1
Clinic of Radiotherapy and Radiation Oncology, University Hospital Basel, Basel, Switzerland.
2
CureVac AG, Tübingen, Germany.
3
Hospital of St Gallen, St Gallen and University of Bern, Bern, Switzerland.
4
University Hospital Frankfurt, Frankfurt, Germany.
5
Cantonal Hospital of Winterthur, Winterthur, Switzerland.
6
Hospital Graubünden, Chur, Switzerland.
7
Medical Department, Center for Oncology and Hematology, Wilhelminenspital, Wien, Austria.
8
University Hospital Innsbruck, Innsbruck, Austria.
9
Department of Internal Medicine III, University Medical Center Mainz, Mainz, Germany.
10
Thoraxklinik Heidelberg gGmbH, Heidelberg, Germany.
11
Klinik für Allg Innere Medizin, Onkolologie/ Hämatologie, Gastroenterologie, Infektiologie, Esslingen, Germany.
12
Department Hematology and Oncology, Pius Hospital University, Oldenburg, Germany.
13
Department Internal Medicine-Oncology, Medical Campus University of Oldenburg, Oldenburg, Germany.
14
eTheRNA Immunotherapies NV, Niel, Belgium.
15
Medical Oncology, University Hospital Basel, Basel, Switzerland. Alfred.Zippelius@usb.ch.

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

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