A Study to Investigate the Novel Agent BNT111 and Cemiplimab in Combination or as Single Agents in Patients With Advanced Melanoma That Has Not Responded to Other Forms of Treatment

Open-label, Randomized Phase II Trial With BNT111 and Cemiplimab in Combination or as Single Agents in Patients With Anti-PD-1-refractory/Relapsed, Unresectable Stage III or IV Melanoma

Status

Completed

Phases

Phase 2

Study type

Interventional

Source

ClinicalTrials.gov

Registry ID

NCT04526899

Enrollment

184

Registered

2020-08-26

Start date

2021-05-19

Completion date

2025-11-24

Last updated

2026-01-08

For informational purposes only — not medical advice. Sourced from public registries and may not reflect the latest updates. Terms

Conditions

Melanoma Stage III, Melanoma Stage IV, Unresectable Melanoma

Keywords

Cancer vaccine, Melanoma, Checkpoint inhibitor, Libtayo®, BNT111, Cemiplimab, RNA vaccine

Brief summary

This is an open-label, randomized, multi-site, Phase II, interventional trial designed to evaluate the efficacy, tolerability, and safety of BNT111 + cemiplimab in anti-programmed death protein 1 (PD-1)/anti-programmed death ligand 1 (PD-L1)-refractory/relapsed patients with unresectable Stage III or IV melanoma. The contributions of BNT111 and cemiplimab will be delineated in single agent calibrator arms. Patients will be randomized in a 2:1:1 ratio to Arm 1 (BNT111 + cemiplimab) and calibrator Arm 2 (BNT111 monotherapy), and Arm 3 (cemiplimab monotherapy). Patients in single agent calibrator arms (Arms 2 and 3), who experience centrally verified disease progression under single agent treatment, may be offered addition of the other compound to the ongoing treatment after re-consent.

Interventions

BIOLOGICALBNT111

IV injection

BIOLOGICALCemiplimab

IV infusion

Study design

Allocation

RANDOMIZED

Intervention model

PARALLEL

Primary purpose

TREATMENT

Masking

NONE

Eligibility

Sex/Gender

ALL

Age

18 Years to No maximum

Healthy volunteers

Inclusion criteria

* Patients must sign the written informed consent form (ICF) before any screening procedure. * Patients must be aged \>=18 years on the date of signing the informed consent. * Patients must be willing and able to comply with scheduled visits, treatment schedule, laboratory tests, and other requirements of the trial. * Patients must have histologically confirmed unresectable Stage III or IV (metastatic) cutaneous melanoma and measurable disease by RECIST v1.1. * Patients must have confirmed disease progression on/after an approved anti-PD-1/PD-L1 regimen for melanoma as defined by RECIST v1.1. 1. Previous exposure to approved anti-PD-1/PD-L1 containing regimen for at least 12 consecutive weeks and 2. Current radiological progression to be confirmed by two scans 4 to 12 weeks apart. If progression is accompanied by new symptoms, or deterioration of performance status not attributed to toxicity, one scan is sufficient and 3. Inclusion into this trial must be within 6 months of confirmation of disease progression on anti-PD-1/PD-L1 treatment, regardless of any intervening therapy. * Patients should have received at least one but no more than five lines of prior therapy for advanced disease. * Patients must be able to tolerate additional anti-PD-1/PD-L1 therapy (i.e., did not permanently discontinue anti-PD-1/PD-L1 therapy due to toxicity). * Patients must have known B-Raf proto-oncogene (BRAF) mutation status. * Patients with BRAF V600-positive tumor(s) should have received prior treatment with a BRAF inhibitor (alone or in combination with a mitogen-activated protein kinase kinase \[MEK\] inhibitor). * Note: Considering the possible negative impact of a prior BRAF/MEK therapy on immune system targeting therapies, patients with BRAF V600-positive tumors with no clinically significant tumor-related symptoms or evidence of rapid PD may be eligible for participation. This should be based on investigator assessment AND provided they are ineligible for, intolerant to, or have refused BRAF V600 mutation targeted therapy after receiving the information on possible other therapies including BRAF/MEK inhibitor-based therapy during the informed consent process. * Patients must have an Eastern Cooperative Oncology Group performance status (PS) \<=1. * Adequate bone marrow function, as defined by hematological parameters (as defined in the protocol). * Patients must have serum lactate dehydrogenase \<= upper limit of normal. * Patient should have adequate hepatic function, as defined in the protocol. * Patient should have adequate kidney function, assessed by the estimated glomerular filtration rate \>= 30 mL/min using the chronic kidney disease epidemiology collaboration equation. * Patient should be stable with adequate coagulation, as defined in the protocol. * Patients must provide the following biopsy samples: 1. All patients: must provide a tumor tissue sample (formalin fixed paraffin-embedded \[FFPE\] blocks/slides) from a fresh biopsy collected before Visit Cycle1 Day1, or archival tissue. The archival tissue can be an FFPE block (not older than 3 years) or freshly cut slides (special storage conditions and immediate shipment to specialty lab are required), preferably derived from advanced disease stage. 2. Patients at selected trial sites: After additional consent, patients must be amenable to pre-treatment and on-treatment peripheral blood mononuclear cell (PBMC) sampling and optional biopsy. If amenable, patients should provide a PBMC sample and optionally a biopsy which contains tumor tissue after failure/stop of last prior trial treatment. * Women of childbearing potential (WOCBP) must have a negative serum (beta-human chorionic gonadotropin \[beta-hCG\]) at screening. Patients that are postmenopausal or permanently sterilized can be considered as not having reproductive potential. Female patients of reproductive potential must agree to use highly effective contraception during and for 6 months after the last trial drug administration. * WOCBP must agree not to donate eggs (ova, oocytes) for the purposes of assisted reproduction during trial starting at screening, during the trial and for 6 months after receiving the last trial treatment. * A man who is sexually active with a WOCBP and has not had a vasectomy must agree to use a barrier method of birth control, e.g., either condom with spermicidal foam/gel/film/cream/suppository or partner with occlusive cap (diaphragm or cervical/vault caps) with spermicidal foam/gel/film/cream/suppository, and all men must also not donate sperm during the trial and for 6 months after receiving the last trial treatment.

Exclusion criteria

* Patients must not be pregnant or breastfeeding. * Patients must not have history of uveal, acral, or mucosal melanoma. * Patients must have no ongoing or recent evidence (within the last 5 years) of significant autoimmune disease that required treatment with systemic immunosuppressive treatments which may pose a risk for irAEs. * Note: Patients with autoimmune-related hyperthyroidism, autoimmune-related hypothyroidism who are in remission, or on a stable dose of thyroid-replacement hormone, vitiligo, or psoriasis may be included. * Patients must have no known primary immunodeficiencies, either cellular (e.g., DiGeorge syndrome, T cell-negative severe combined immunodeficiency \[SCID\]) or combined T and B cell immunodeficiencies (e.g., T and -B negative SCID, Wiskott Aldrich syndrome, ataxia telangiectasia, common variable immunodeficiency). * Patients with uncontrolled type 1 diabetes mellitus or with uncontrolled adrenal insufficiency are not eligible. * Patients must have no uncontrolled infection with human immunodeficiency virus (HIV), hepatitis B or hepatitis C infection; or diagnosis of immunodeficiency that is related to, or results in chronic infection. Mild cancer-related immunodeficiency (such as immunodeficiency treated with gamma globulin and without chronic or recurrent infection) is allowed. 1. Patients with known HIV who have controlled infection (undetectable viral load and CD4 count above 350 either spontaneously or on a stable anti-viral regimen) are permitted. For patients with controlled HIV infection, monitoring will be performed per local standards. 2. Patients with known hepatitis B virus (HBV) who have controlled infection (serum hepatitis B virus DNA polymerase chain reaction (PCR) that is below the limit of detection AND receiving anti-viral therapy for hepatitis B) are permitted. Patients with controlled infections must undergo periodic monitoring of HBV DNA per local standards. Patients must remain on anti-viral therapy for at least 6 months beyond the last dose of trial treatment. 3. Patients who are known hepatitis C virus (HCV) antibody positive who have controlled infection (undetectable HCV RNA by PCR either spontaneously or in response to a successful prior course of anti-HCV therapy) are permitted. 4. Patients with HIV or hepatitis must have their disease reviewed by the specialist (e.g., infectious disease specialist or hepatologist) managing this disease prior to commencing and throughout the duration of their participation in the trial. * Patients with another primary malignancy that has not been in complete remission for at least 2 years, with the exception of those with a negligible risk of metastasis, progression or death (such as adequately treated carcinoma in situ of the cervix, basal or squamous cell skin cancer, localized prostate cancer, non-invasive, superficial bladder cancer or breast ductal carcinoma in situ). * Current use or use within 3 months prior to trial enrollment of systemic immune suppression including: 1. use of chronic systemic steroid medication (up to 5 mg/day prednisolone equivalent is allowed); patients using physiological replacement doses of prednisone for adrenal or pituitary insufficiency are eligible, 2. other clinically relevant systemic immune suppression. * Treatment with other anti-cancer therapy including chemotherapy, radiotherapy, investigational, or biological cancer therapy within 3 weeks prior to the first dose of trial treatment (6 weeks for nitrosureas). Adjuvant hormonotherapy used for breast cancer in long term remission is allowed. * Current evidence of ongoing National Cancer Institute Common Terminology Criteria for Adverse Events version 5.0 (NCI-CTCAE v5.0) Grade \> 1 toxicity of prior therapies before the start of treatment, with the exception of hair loss, hearing loss, Grade 2 peripheral neuropathy, or laboratory abnormalities not considered clinically significant per investigator's discretion, and those Grade 2 toxicities listed as permitted in other eligibility criteria. * Patients who have a local infection (e.g., cellulitis, abscess) or systemic infection (e. g., pneumonia, septicemia) which requires systemic antibiotic treatment within 2 weeks prior to the first dose of trial treatment. * Patients who have had a splenectomy. * Patients who have had major surgery (e.g., requiring general anesthesia) within 4 weeks before screening, have not fully recovered from surgery, or have a surgery planned during the time of trial participation. * Current evidence of new or growing brain or spinal metastases during screening. Patients with leptomeningeal disease are excluded. Patients with known brain or spinal metastases may be eligible if they: 1. had radiotherapy or another appropriate therapy for the brain or spinal bone metastases, 2. have no neurological symptoms that can be attributed to the current brain lesions, 3. have stable brain or spinal disease on the computed tomography or magnetic resonance imaging scan within 4 weeks before randomization (confirmed by stable lesions on two scans at least 4 weeks apart, the second scan can be carried out during screening), 4. do not require steroid therapy within 14 days before the first dose of trial treatment, 5. spinal bone metastases are allowed, unless imminent fracture or cord compression is anticipated. * History or current evidence of significant cardiovascular disease including, but not limited to: 1. angina pectoris requiring anti-anginal medication, uncontrolled cardiac arrhythmia(s), severe conduction abnormality, or clinically significant valvular disease, 2. QTc (F) prolongation \> 480 ms, 3. arterial thrombosis or pulmonary embolism within ≤ 6 months before the start of treatment, 4. myocardial infarction within ≤ 6 months before the start of treatment, 5. pericarditis (any NCI-CTCAE grade), pericardial effusion (NCI-CTCAE Grade \>= 2), non-malignant pleural effusion (NCI-CTCAE Grade \>=2) or malignant pleural effusion (NCI-CTCAE Grade \>= 3) within \<= 6 months before the start of treatment, 6. Grade \>= 3 symptomatic congestive heart failure (CHF) or New York Heart Association (NYHA) criteria Class \>= II within \<=6 months before the start of treatment. * Patients who have received a live vaccine within 28 days of planned start of trial therapy. * Known hypersensitivity to the active substances or to any of the excipients. * Presence of a severe concurrent illness or other condition (e.g., psychological, family, sociological, or geographical circumstances) that does not permit adequate follow-up and compliance with the protocol. * Prior treatment with BNT111 and/or with cemiplimab. Inclusion criteria for entering add-on therapy * Patients must have confirmed disease progression on monotherapy in Arm 2 or 3 of the trial. 1. An initial radiological progression needs to be verified by BICR. 2. Radiological progression to be confirmed by two scans 4 to 12 weeks apart unless initial progression is accompanied by new symptoms, or deterioration of PS not attributed to toxicity, in which case one scan is sufficient. * Patients must sign a new ICF to continue with add-on therapy. Informed consent must be documented before any add-on-specific procedure is performed. * WOCBP must have a negative serum (beta-hCG) at baseline. Patients that are postmenopausal or permanently sterilized can be considered as not having reproductive potential. * Female patients of reproductive potential must agree to use adequate contraception during and for 6 months after the last trial drug administration. * WOCBP must agree not to donate eggs (ova, oocytes) for the purposes of assisted reproduction during trial starting at screening, during the trial and for 6 months after receiving the last trial treatment. * A man who is sexually active with a WOCBP and has not had a vasectomy must agree to use a barrier method of birth control, e.g., either condom with spermicidal foam/gel/film/cream/suppository or partner with occlusive cap (diaphragm or cervical/vault caps) with spermicidal foam/gel/film/cream/suppository, and all men must also not donate sperm during the trial and for 6 months after receiving the last trial treatment.

Design outcomes

Primary

Measure	Time frame	Description
Arm 1: Objective Response Rate (ORR)	Up to 24 months	ORR was defined as the percentage of participants in whom a complete response (CR) or partial response (PR) according to response evaluation criteria in solid tumors version 1.1 (RECIST v1.1) was observed as best overall response by blinded independent central review (BICR). Per RECIST 1.1 criteria, CR defined as the disappearance of all target lesions and PR was defined as the \>=30% decrease in the sum of the longest diameter of target lesions.

Secondary

Measure	Time frame	Description
Duration of Response (DOR) As Assessed by Blinded Independent Central Review (BICR)	Up to 24 Months	DOR is defined as the time from first objective response (CR or PR) to first occurrence of objective tumor progression (progressive disease, PD) by BICR or death from any cause (whichever occurs first). Data for this outcome measure will be reported at the time of final results posting.
Disease Control Rate (DCR) As Assessed by BICR	Up to 24 months	DCR is defined as the percentage of participants in whom a CR, PR or stable disease (SD; assessed at least 6 weeks after first dose) is observed as best overall response by BICR. Data for this outcome measure will be reported at the time of final results posting.
Time to Response (TTR) As Assessed by BICR	Up to 24 months	TTR is defined as the time from randomization to the first objective tumor response (CR or PR) by BICR. Data for this outcome measure will be reported at the time of final results posting.
Progression-Free Survival (PFS) As Assessed by BICR	Up to 24 Months	PFS is defined as the time from randomization to first objective tumor progression (PD) by BICR or death from any cause (whichever occurs first). Data for this outcome measure will be reported at the time of final results posting.
Objective Response Rate (ORR) As Assessed by the Investigator	Up to 24 months	ORR is defined as the percentage of participants in whom a CR or PR according to RECIST v1.1 observed as best overall response by investigator. Data for this outcome measure will be reported at the time of final results posting.
Duration of Response (DOR) As Assessed by the Investigator	Up to 24 Months	DOR is defined as the time from first objective response (CR or PR) to first occurrence of objective tumor progression (progressive disease, PD) by BICR or death from any cause (whichever occurs first). Data for this outcome measure will be reported at the time of final results posting.
Disease Control Rate (DCR) As Assessed by the Investigator	Up to 24 months	DCR defined as the percentage of participants in whom a CR, PR or stable disease (SD; assessed at least 6 weeks after first dose) is observed as best overall response by investigator. Data for this outcome measure will be reported at the time of final results posting.
Time to Response (TTR) As Assessed by the Investigator	Up to 24 months	TTR is defined as the time from randomization to the first objective tumor response (CR or PR) as assessed by investigator. Data for this outcome measure will be reported at the time of final results posting.
Progression-Free Survival (PFS) As Assessed by the Investigator	Up to 24 Months	PFS is defined as the time from randomization to first objective tumor progression (PD) by investigator or death from any cause (whichever occurs first). Data for this outcome measure will be reported at the time of final results posting.
Arm 1: Overall Survival (OS)	Up to 48 months	OS is defined as the time from randomization to death from any cause. Data for this outcome measure will be reported at the time of final results posting.
Number of Participants With Treatment-Emergent Adverse Events (TEAEs)	Up to 27 months	A treatment-emergent adverse event (TEAE) is defined as any AE with an onset date on or after the first administration of trial treatment (if the AE was absent before the first administration of trial treatment) or worsened after the first administration of trial treatment (if the AE was present before the first administration of trial treatment). Data for this outcome measure will be reported at the time of final results posting.
Number of Participants With Immune-Related Adverse Events (irAE)	Up to 27 months	AEs related to the use of immune checkpoint inhibitor (ICI) therapy are defined as immune-related (IR) AEs (irAEs). Data for this outcome measure will be reported at the time of final results posting.
Number of Participants Reporting Dose Reduction and Discontinuation Due to TEAE	Up to 27 months	Participants with dose reduction and discontinuation due to TEAE will be reported. Data for this outcome measure will be reported at the time of final results posting.
Change From Baseline in Laboratory Parameters Values: Hematology: Basophils	From Baseline up to 25 months	Blood samples will be collected for the assessment of hematology parameters. Data for this outcome measure will be reported at the time of final results posting.
Change From Baseline in Laboratory Parameters Values: Hematology: Eosinophils	From Baseline up to 25 months	Blood samples will be collected for the assessment of hematology parameters. Data for this outcome measure will be reported at the time of final results posting.
Change From Baseline in Laboratory Parameters Values: Hematocrit	From Baseline up to 25 months	Blood samples will be collected for the assessment of hematology parameters. Data for this outcome measure will be reported at the time of final results posting.
Change From Baseline in Laboratory Parameters Values: Hemoglobin	From Baseline up to 25 months	Blood samples will be collected for the assessment of hematology parameters. Data for this outcome measure will be reported at the time of final results posting.
Change From Baseline in Laboratory Parameters Values: Hematology: Lymphocytes	From Baseline up to 25 months	Blood samples will be collected for the assessment of hematology parameters. Data for this outcome measure will be reported at the time of final results posting.
Change From Baseline in Laboratory Parameters Values: Clinical Chemistry: Albumin	From Baseline up to 25 months	Blood samples will be collected for the assessment of clinical chemistry parameters. Data for this outcome measure will be reported at the time of final results posting.
Change From Baseline in Laboratory Parameters Values: Clinical Chemistry: Alkaline Phosphatase	From Baseline up to 25 months	Blood samples will be collected for the assessment of clinical chemistry parameters. Data for this outcome measure will be reported at the time of final results posting.
Change From Baseline in Laboratory Parameters Values: Clinical Chemistry: Alanine Aminotransferase	From Baseline up to 25 months	Blood samples will be collected for the assessment of clinical chemistry parameters. Data for this outcome measure will be reported at the time of final results posting.
Change From Baseline in Laboratory Parameters Values: Clinical Chemistry: Amylase	From Baseline up to 25 months	Blood samples will be collected for the assessment of clinical chemistry parameters. Data for this outcome measure will be reported at the time of final results posting.
Change From Baseline in Laboratory Parameters Values: Clinical Chemistry: Aspartate Aminotransferase	From Baseline up to 25 months	Blood samples will be collected for the assessment of clinical chemistry parameters. Data for this outcome measure will be reported at the time of final results posting.
Change From Baseline in Laboratory Parameters Values: Clinical Chemistry: Bilirubin	From Baseline up to 25 months	Blood samples will be collected for the assessment of clinical chemistry parameters. Data for this outcome measure will be reported at the time of final results posting.
Change From Baseline in Laboratory Parameters Values: Clinical Chemistry: Creatine Kinase	From Baseline up to 25 months	Blood samples will be collected for the assessment of clinical chemistry parameters. Data for this outcome measure will be reported at the time of final results posting.
Change From Baseline in Laboratory Parameters Values: Clinical Chemistry: Creatinine	From Baseline up to 25 months	Blood samples will be collected for the assessment of clinical chemistry parameters. Data for this outcome measure will be reported at the time of final results posting.
Change From Baseline in Laboratory Parameters Values: Clinical Chemistry: C-Reactive Protein	From Baseline up to 25 months	Blood samples will be collected for the assessment of clinical chemistry parameters. Data for this outcome measure will be reported at the time of final results posting.
Change From Baseline in Laboratory Parameters Values: Coagulation Factors: Activated Partial Thromboplastin Time	From Baseline up to 25 months	Blood samples will be collected for the assessment of coagulation factors. Data for this outcome measure will be reported at the time of final results posting.
Change From Baseline in Laboratory Parameters Values: Coagulation Factors: Prothrombin Time	From Baseline up to 25 months	Blood samples will be collected for the assessment of coagulation factors. Data for this outcome measure will be reported at the time of final results posting.
Change From Baseline in Laboratory Parameters Values: Endocrine Tests: Thyroxine	From Baseline up to 25 months	Blood samples will be collected for the assessment of endocrine tests. Data for this outcome measure will be reported at the time of final results posting.
Change From Baseline in Laboratory Parameters Values: Urinalysis: pH	From Baseline up to 25 months	Urine samples will be collected for the assessment of pH. Data for this outcome measure will be reported at the time of final results posting.
Number of Participants With Clinically Significant Abnormalities in Laboratory Parameters	Up to 25 months	Participants with clinically significant abnormalities in laboratory parameters will be reported. Data for this outcome measure will be reported at the time of final results posting.
Change From Baseline in Vital Signs Parameters: Systolic Blood Pressure	From Baseline up to 25 months	Systolic blood pressure (in mmHg) will be assessed. Data for this outcome measure will be reported at the time of final results posting.
Change From Baseline in Vital Signs Parameters: Diastolic Blood Pressure	From Baseline up to 25 months	Diastolic blood pressure (in mmHg) will be assessed. Data for this outcome measure will be reported at the time of final results posting.
Change From Baseline in Vital Signs Parameters: Heart Rate	From Baseline up to 25 months	Heart rate (in beats per minute) will be assessed. Data for this outcome measure will be reported at the time of final results posting.
Change From Baseline in Vital Signs Parameters: Respiratory Rate	From Baseline up to 25 months	Respiratory Rate (in breaths per minute) will be assessed. Data for this outcome measure will be reported at the time of final results posting.
Change From Baseline in Vital Signs Parameters: Body Temperature	From Baseline up to 25 months	Body Temperature (in degree Celsius) will be assessed. Data for this outcome measure will be reported at the time of final results posting.
Number of Participants With Clinically Significant Abnormalities in Vital Signs	Up to 25 months	Participants with clinically significant abnormalities in vital sign parameters will be reported. Data for this outcome measure will be reported at the time of final results posting.
Arms 2 & 3: Objective Response Rate (ORR)	Up to 24 Months	ORR is defined as the percentage of participants in whom a CR or PR according to RECIST v1.1 observed as best overall response by BICR. Data for this outcome measure will be reported at the time of final results posting.
Change From Baseline in EORTC QLQ-C30 Functional Scales Score	From Baseline up to 25 months	The EORTC QLQ-C30 questionnaire incorporates nine multi-item scales: 5 functional scales (physical, cognitive, role, emotional, and social); 3 symptom scales (pain, fatigue, and appetite loss) and a Global Health Status/QoL scale. EORTC QLQ-C30 Physical Functioning Score is a questionnaire to assess quality of life of cancer patients. It is composed of 30 items, multi-item measure (28 items) and 2 single-item measures. For the multiple item measure, 4-point scale is used and the score for each item range from 1 = not at all to 4 = very much. Higher scores indicate worsening of symptoms. Data for this outcome measure will be reported at the time of final results posting.
Changes From Baseline in EORTC QLQ-C30 Symptoms Scales Score	From Baseline up to 25 months	The EORTC QLQ-C30 questionnaire incorporates nine multi-item scales: 5 functional scales (physical, cognitive, role, emotional, and social); 3 symptom scales (pain, fatigue, and appetite loss) and a Global Health Status/QoL scale. Each item, except Global Health Status, is answered on a four-point scale (1-4): 1-not at all, 2-a little, 3-quite a bit, 4-very much. Each scale (symptom scale \[pain, fatigue, and appetite loss\] and Global Health Status/Quality of Life \[QoL\] scale) was linearly transformed to be in range from 0-100 where a higher score represents good health status, while lower scores indicate poor health status. Data for this outcome measure will be reported at the time of final results posting.
Time to First Clinically Meaningful Deterioration in Global Health Status Score as Measured by EORTC QLQ-C30	Up to 25 months	Time to first clinically meaningful deterioration in global health status score as measured by EORTC QLQ-C30 will be reported. Data for this outcome measure will be reported at the time of final results posting.
Time to First Clinically Meaningful Deterioration in Symptoms and Functioning as Measured by EORTC QLQ-C30	Up to 25 months	Time to first clinically meaningful deterioration in symptoms and functioning as measured by EORTC QLQ-C30 will be reported. Data for this outcome measure will be reported at the time of final results posting.
Change From Baseline in European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 Items (EORTC QLQ-C30) Global Health Status Total Score	From Baseline up to 25 months	Mean change from baseline in the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 Items (EORTC QLQ-C30) Global Health Status Score will be reported. Each item, except Global Health Status, is answered on a four-point scale (1-4): 1-not at all, 2-a little, 3-quite a bit, 4-very much. Response to Global Health Status is measured on a 1 to 7 scale. 1 being very poor and 7 being excellent. Positive changes indicated better health status or functioning, and negative changes indicated worsening of health status or functioning. Scale scores range from 0 to 100. Raw data was linearly transformed to be in a range from 0-100 where a higher score represents good health status, while lower scores indicate poor health status. Data for this outcome measure will be reported at the time of final results posting.

Countries

Australia, Germany, Italy, Poland, Spain, United Kingdom, United States

Participant flow

Recruitment details

In total,184 participants were randomized to treatment but 3 participants (2 participants in Arm 1 and 1 participant in Arm 3, respectively) did not receive the study treatment.

Pre-assignment details

Participants in Arms 2 and 3 who experienced centrally verified disease progression under single agent treatment were offered addition of the other compound to the ongoing treatment after re-consent. Participants of the two add-on treatment arms are a subset of the participants in Arm 2 and Arm 3, respectively.

Participants by arm

Arm	Count
Arm 1: BNT111 + Cemiplimab Participants received BNT111 IV infusion once-weekly starting on Day 1 of Cycle 1 for the first 6 weeks, followed by once every 3 weeks (each cycle duration=21 days), along with Cemiplimab once every 3 weeks for up to 24 months or until confirmed progression of disease, withdrawal of consent or unacceptable toxicity, whichever occurs first.	94
Arm 2: BNT111 Monotherapy Participants received BNT111 IV infusion once-weekly starting on Day 1 of Cycle 1 for the first 6 weeks (each cycle duration=21 days), followed by once every 3 weeks for up to 24 months or until confirmed progression of disease, withdrawal of consent or unacceptable toxicity, whichever occurs first. Participants in Arm 2 who experienced disease progression under monotherapy were eligible to continue with add-on therapy and received Cemiplimab once every 3 weeks as add-on treatment and BNT111 was continued according to the planned schedule. Participants received a total of 6 weekly injections during the initial trial treatment and the add-on therapy before moving to a once every 3-week schedule of injections.	46
Arm 3: Cemiplimab Monotherapy Participants received Cemiplimab IV infusion once every 3 weeks starting on Day 1 of Cycle 1 for up to 24 months or until confirmed progression of disease, withdrawal of consent or unacceptable toxicity, whichever occurs first. Participants in Arm 3 who experienced disease progression under monotherapy were eligible to continue with add-on therapy and received BNT111 once weekly for the first 6 weeks as add-on therapy, followed by treatments once every 3 weeks. Cemiplimab was given once every 3 weeks.	44
Total	184

Withdrawals & dropouts

Period	Reason	FG000	FG001	FG002
Overall Study	Death	33	17	13
Overall Study	Investigator's decision	1	0	0
Overall Study	Lost to Follow-up	3	3	1
Overall Study	On-Treatment	19	10	12
Overall Study	Other	1	0	0
Overall Study	Survival Follow-up	34	14	16
Overall Study	Withdrawal by Subject	3	2	2

Baseline characteristics

Characteristic	Arm 1: BNT111 + Cemiplimab	Arm 2: BNT111 Monotherapy	Arm 3: Cemiplimab Monotherapy	Total
Age, Continuous	62.9 years STANDARD_DEVIATION 13.54	63.1 years STANDARD_DEVIATION 13.89	61.9 years STANDARD_DEVIATION 15.78	62.7 years STANDARD_DEVIATION 14.12
Ethnicity (NIH/OMB) Hispanic or Latino	3 Participants	2 Participants	2 Participants	7 Participants
Ethnicity (NIH/OMB) Not Hispanic or Latino	85 Participants	41 Participants	41 Participants	167 Participants
Ethnicity (NIH/OMB) Unknown or Not Reported	6 Participants	3 Participants	1 Participants	10 Participants
Race (NIH/OMB) American Indian or Alaska Native	0 Participants	0 Participants	0 Participants	0 Participants
Race (NIH/OMB) Asian	0 Participants	0 Participants	0 Participants	0 Participants
Race (NIH/OMB) Black or African American	0 Participants	0 Participants	00 Participants	0 Participants
Race (NIH/OMB) More than one race	0 Participants	0 Participants	0 Participants	0 Participants
Race (NIH/OMB) Native Hawaiian or Other Pacific Islander	0 Participants	0 Participants	0 Participants	0 Participants
Race (NIH/OMB) Unknown or Not Reported	5 Participants	2 Participants	0 Participants	7 Participants
Race (NIH/OMB) White	89 Participants	44 Participants	44 Participants	177 Participants
Sex: Female, Male Female	34 Participants	17 Participants	19 Participants	70 Participants
Sex: Female, Male Male	60 Participants	29 Participants	25 Participants	114 Participants

Adverse events

Event type	EG000 affected / at risk	EG001 affected / at risk	EG002 affected / at risk	EG003 affected / at risk	EG004 affected / at risk
deaths Total, all-cause mortality	33 / 94	6 / 46	6 / 44	11 / 25	7 / 22
other Total, other adverse events	89 / 92	43 / 46	33 / 43	22 / 25	22 / 22
serious Total, serious adverse events	30 / 92	8 / 46	11 / 43	6 / 25	7 / 22

Outcome results

Primary

Arm 1: Objective Response Rate (ORR)

ORR was defined as the percentage of participants in whom a complete response (CR) or partial response (PR) according to response evaluation criteria in solid tumors version 1.1 (RECIST v1.1) was observed as best overall response by blinded independent central review (BICR). Per RECIST 1.1 criteria, CR defined as the disappearance of all target lesions and PR was defined as the \>=30% decrease in the sum of the longest diameter of target lesions.

Time frame: Up to 24 months

Population: Analysis was performed on modified intent to treat (mITT) set that included all participants who were randomized and had at least one dose of trial treatment and had a baseline and at least one post randomization tumor response assessment. Data for this outcome measure was planned for Arm 1 only and for other arms, results will be reported in secondary outcome measures after final analysis.

Arm	Measure	Value (NUMBER)
Arm 1: BNT111 + Cemiplimab	Arm 1: Objective Response Rate (ORR)	18.0 percentage of participants

p-value: 0.01481-sided exact binomial test

Secondary

Arm 1: Overall Survival (OS)

OS is defined as the time from randomization to death from any cause. Data for this outcome measure will be reported at the time of final results posting.

Time frame: Up to 48 months

Secondary

Arms 2 & 3: Objective Response Rate (ORR)

ORR is defined as the percentage of participants in whom a CR or PR according to RECIST v1.1 observed as best overall response by BICR. Data for this outcome measure will be reported at the time of final results posting.

Time frame: Up to 24 Months

Secondary

Change From Baseline in EORTC QLQ-C30 Functional Scales Score

The EORTC QLQ-C30 questionnaire incorporates nine multi-item scales: 5 functional scales (physical, cognitive, role, emotional, and social); 3 symptom scales (pain, fatigue, and appetite loss) and a Global Health Status/QoL scale. EORTC QLQ-C30 Physical Functioning Score is a questionnaire to assess quality of life of cancer patients. It is composed of 30 items, multi-item measure (28 items) and 2 single-item measures. For the multiple item measure, 4-point scale is used and the score for each item range from 1 = not at all to 4 = very much. Higher scores indicate worsening of symptoms. Data for this outcome measure will be reported at the time of final results posting.