Phase 1/2 Study of Combination Immunotherapy and Messenger Ribonucleic Acid (mRNA) Vaccine in Subjects With NSCLC

This is an open-label, multicenter, 2-arm study to evaluate the safety and preliminary efficacy of the addition of a vaccine therapy to 1 or 2 checkpoint inhibitors for NSCLC.

Arm A: messenger ribonucleic acid (mRNA) Vaccine \[BI 1361849 (formerly CV9202)\] + anti-programmed death ligand 1 (PD-L1) antibody \[durvalumab\]

Arm B: messenger ribonucleic acid (mRNA) Vaccine \[BI 1361849\] + anti-programmed death ligand 1 (PD-L1) \[durvalumab\] + anti-cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) antibody \[tremelimumab\]

The run-in evaluation phase is followed by an expansion phase in which the cohort is expanded to 20 subjects (inclusive of subjects from the run-in).

This was a Phase 1/2, open-label, multicenter, 2-arm study to evaluate the safety and preliminary efficacy of the addition of a vaccine therapy to 1 or 2 checkpoint inhibitors in subjects with NSCLC.

Up to 56 subjects were planned for enrollment from up to 8 clinical sites in 2 arms:

Arm A: mRNA Vaccine \[BI 1361849 (formerly CV9202)\] + anti-PD-L1 antibody \[durvalumab\]

Arm B: mRNA Vaccine \[BI 1361849\] + anti-PD-L1 \[durvalumab\] + anti-CTLA-4 antibody \[tremelimumab\]

Subjects must have had histologically confirmed metastatic NSCLC. For subjects with known EGFR or ALK/ROS-1 mutations, prior therapy must have included an EGFR tyrosine kinase inhibitor or ALK/ROS-1 inhibitor, respectively. Subjects may have had 1 prior line of anti-PD-1/PD-L1 therapy and must not have had progression at or before 12 weeks after start of the prior anti-PD-1/PD-L1 treatment.

Eligibility Criteria:
Inclusion Criteria

1. Histologic confirmation of metastatic NSCLC. For subjects with known EGFR or ALK/ROS-1 mutations, prior therapy must have included an EGFR tyrosine kinase inhibitor or ALK/ROS-1 inhibitor, respectively. Subjects may have had 1 prior line of anti-PD-1/PD-L1 therapy. Subjects who received prior anti-PD-1/PD-L1 therapy must have progressed during or after the prior anti-PD-1/PD-L1 therapy treatment, but not prior to Week 12 of treatment.
2. Measurable disease according to RECIST 1.1.
3. Availability of archival (diagnostic) specimens or willing to undergo a pre-treatment biopsy.
4. Subjects with treated brain metastases must have been treated with surgery and/or radiation therapy ≥ 21 days pre-study and must be clinically stable with no requirement for steroids.
5. Laboratory parameters for vital functions should be in the normal range.
6. ECOG Performance Status ≤ 2.
7. Body weight \> 30 kg.

Exclusion Criteria

Subjects may not enter the study if they fulfill any of the following criteria:

1. Treatment with an investigational agent within 4 weeks of starting treatment or prior treatment with anti-CTLA-4 therapy.
2. Active, suspected or prior documented autoimmune disease, clinically significant cardiovascular disease, or clinically uncontrolled hypertension.
3. History of pneumonitis or interstitial lung disease, or any unresolved immune-related adverse events following prior therapy.
4. Major surgery within 4 weeks of starting treatment (or scheduled for surgery during the projected course of the study) or prior cancer vaccine treatment or allogeneic bone marrow transplantation.
5. Subjects who are immunosuppressed, including those with known immunodeficiency or have active infection or other serious illnesses.
6. Active infection including tuberculosis (TB), hepatitis B (HBV), hepatitis C, or human immunodeficiency virus (HIV). Subjects with a past or resolved HBV infection were eligible. Subjects positive for hepatitis C (HCV) antibody were eligible only if polymerase chain reaction was negative for HCV RNA.
7. History of severe allergic reactions to any unknown allergens or components of the study drugs.
8. Uncontrolled intercurrent illness, including but not limited to, ongoing or active infection, bleeding disorders, symptomatic congestive heart failure, uncontrolled hypertension, unstable angina pectoris, cardiac arrhythmia, interstitial lung disease, or serious chronic gastrointestinal conditions associated with diarrhea.
9. Subjects must not have donated blood while on study and for at least 90 days following the last durvalumab treatment or for 6 months after the last dose of tremelimumab (whichever was longer).
10. History of allogeneic organ transplant.
11. History of leptomeningeal carcinomatosis.
12. Active or prior malignancy except for history of other prior malignancy treated with curative intent which, in the opinion of the treating Investigator and the Sponsor, had minimal risk of interfering with safety or efficacy endpoints of the study.
13. Women of childbearing potential who were pregnant as evidenced by positive serum pregnancy test (minimum sensitivity 25 IU/L or equivalent units of human chorionic gonadotropin \[HCG\]) or nursing.
14. Skin disease (e.g., psoriasis) that may prevent intradermal administration of the vaccine into the target areas.