Clinical Trial Evaluating the Safety, Tolerability and Preliminary Efficacy of BNT116 Alone and in Combinations in Patients With Advanced Non-small Cell Lung Cancer

Key Inclusion Criteria:

• Patients must have histologically confirmed NSCLC and measurable disease by RECISTv1.1. Note: Patients in Cohort 1 and Cohort 5 do not have to present with measurabledisease.

1. Patients must present with unresectable Stage III or metastatic Stage IV NSCLCby American Joint Commission on Cancer (AJCC) Cancer Staging Manual, EighthEdition.EXCEPT

2. Patients in Cohort 5 must present with unresectable Stage III NSCLC by AJCCCancer Staging Manual, Eighth Edition before receiving pre-trialchemoradiotherapy.

3. Patients in Cohort 6 with the initial diagnosis of resectable Stage II andStage III NSCLC by AJCC Cancer Staging Manual, Eighth Edition.

• Patients in Cohorts 2, 4, 5, and 6 must be able to tolerate (additional) anti-PD-1therapy (i.e., did not permanently discontinue anti-programmed death protein 1 [PD-1] / programmed death ligand 1 [PD-L1] therapy due to toxicity).

• Patients must have an Eastern Cooperative Oncology Group performance status (ECOG-PS) ≤1, except for patients in Cohorts 1, 4, and 5 who are eligible with anECOG-PS of 0-2.

Cohort-specific inclusion criteria:

Cohort 1:

• Patients' prior therapy must have included at least a PD-1/PD-L1 inhibitor and aplatinum-based chemotherapy regimen as well as one other line of systemic therapy (except if a patient is not candidate for a platinum-based chemotherapy and/orPD-1/PD-L1 inhibitor and/or another line of systemic therapy). Note: Patients newlyenrolled in Cohort 1B under clinical trial protocol v5.0 and subsequent versions ofthe clinical trial protocol must consent to mandatory blood sampling for peripheralblood mononuclear cells (PBMCs).

• Patients who are to start cemiplimab at Cycle 3 must present with PD-L1 expressionof tumor proportion score (TPS) ≥1% in tumor cells (as determined locally).

Cohort 2:

• Patients must present with PD-L1 expression of tumor proportion score (TPS) ≥50% intumor cells (as determined locally prior to inclusion in this trial).

• Patients must present with progressive disease either

1. in the advanced or metastasized stage of NSCLC: while on a PD-1/PD-L1 inhibitortherapy or within 6 months of termination of this treatment as first-linetreatment. Or

2. be refractory to ongoing adjuvant therapy/maintenance treatment after CRT witha PD-1/PD-L1 inhibitor that has been given for at least 3 months in monotherapy (i.e., after an initial combination therapy) before being enrolled into thistrial.

Cohort 3:

• Patients' prior therapy must have included at least a PD-1/PD-L1 inhibitor and aplatinum-based chemotherapy regimen (except if a patient is not candidate for aplatinum-based chemotherapy and/or PD-1/PD-L1 inhibitor).

• Patients must present with progressive disease.

Cohort 4:

• Patients' who are not candidates for chemotherapy as first-line treatment for theadvanced or metastasized stage of NSCLC may be enrolled if presenting with PD-L1expression: TPS ≥1% in tumor cells (as determined locally).

Cohort 5:

• Patients' NSCLC must have been considered unresectable due to patients' conditionand/or tumor-related factors and the patients must have undergone chemoradiotherapybefore entering the trial.

Cohort 6:

• Patients' NSCLC must be considered technically and medically resectable.

• Patients must be considered eligible for neo-adjuvant treatment.

Cohort 7:

• Patients' prior therapy must have included at least a PD-1/PD-L1 inhibitor and aplatinum-based chemotherapy regimen (except if a patient is not a candidate for aplatinum-based chemotherapy and/or PD-1/PD-L1 inhibitor). Note 1: Patients may havereceived prior therapy targeting CTLA-4, lymphocyte-activation gene 3 (LAG-3), Tcell immunoglobulin and immunoreceptor tyrosine-based inhibitory motif [ITIM] domain (TIGIT), vascular endothelial growth factor (VEGF) or VEGF receptor (VEGFR)inhibitor as monotherapy or part of a combination therapy. Note 2: If the patient'sprior therapies included a CTLA-4 inhibitor, the patient must be able to tolerate (additional) treatment with the CTLA-4 inhibitor.

• Patients must present with progressive disease at trial enrollment.

• Patients must consent to mandatory blood sampling for PBMCs.

Cohorts 8 & 9:

• Patients' prior therapy must have included at least a PD-1/PD-L1 inhibitor and aplatinum-based chemotherapy regimen (except if a patient is not a candidate for aplatinum-based chemotherapy and/or PD-1/PD-L1 inhibitor).

• Patients must present with progressive disease at trial enrollment.

Key Exclusion Criteria:

• Ongoing active systemic treatment against NSCLC.

• Presence of a driver mutation for which approved target therapies are availableexcept if the patient is not a candidate for the respective targeted therapy.

• Ongoing or recent evidence (within the last 5 years) of significant autoimmunedisease that required treatment with systemic immunosuppressive treatments which maysuggest risk for immune-related adverse events. Note: Patients withautoimmune-related hyperthyroidism, autoimmune-related hypothyroidism who are inremission, or on a stable dose of thyroid-replacement hormone, vitiligo, orpsoriasis may be included.

• Current evidence of new or growing brain or spinal metastases during screening.Patients with leptomeningeal disease are excluded. Patients with known brain orspinal metastases may be eligible for all Cohorts, except for Cohort 5 and 6, ifthey:

• had radiotherapy or another appropriate therapy for the brain or spinal metastases,AND

• have no neurological symptoms that can be attributed to the current brain lesions,AND

• have stable brain or spinal disease on the computed tomography (CT) or magneticresonance imaging (MRI) scan within 4 weeks before signing the informed consent (confirmed by stable lesions on two scans at least 4 weeks apart), AND

• do not require steroid therapy for the treatment of brain or spinal metastaseswithin 14 d before the first dose of trial treatment. Note: Spinal bone metastases (i.e., of the vertebrae) are allowed, unless imminent fracture or cord compressionis anticipated.

• Systemic immune suppression:

• Current use of chronic systemic steroid medication (≤5 mg/day prednisoloneequivalent is allowed); patients using physiological replacement doses of prednisonefor adrenal or pituitary insufficiency are eligible. Note: Steroid medication givenfor supportive or prophylactic reasons during CRT for patients in Cohort 5 needs tobe tapered to ≤5 mg/day prednisolone equivalent at latest on the day before thetrial treatment starts.

• Other clinically relevant systemic immune suppression within the last 3 monthsbefore trial enrollment.

• Known history of seropositivity for human immunodeficiency virus (HIV) with CD4+T-cell (CD4+) counts <350 cells/µL and with a history of acquired immunodeficiencysyndrome (AIDS)-defining opportunistic infections.

• Prior splenectomy.

• History/risk of interstitial lung disease or low baseline lung function (baselinepulse oximetry of less than 92% oxygen saturation [SpO2] without additional oxygen).

NOTE: Other protocol defined Inclusion/Exclusion criteria may apply to all or some patients depending on the cohort.