Inclusion Criteria: 

• Have given informed consent by signing and dating an ICF before initiation of any trial-specific procedures.
• Are willing and able to comply with scheduled visits, treatment schedule, the planned trial assessments, lifestyle restrictions, and other requirements of the trial. This includes that they are able to understand and follow trial-related instructions.
• Aged ≥ 18 years at the time of giving informed consent.
• Histological or cytological confirmed unresectable advanced/metastatic lung cancer. Histological classification may be based on tumor samples prior to metastatic disease. Participants with mixed histology must be classified based on the main component. Participants with NSCLC are eligible with any or no PD-L1 expression. Participants with AGA-positive disease must have received targeted therapy prior to enrollment in this trial.
• Have measurable disease defined by RECIST 1.1 (see Section 8.3.1 for details).
• All participants (except for participants with SCLC) must provide a tumor tissue sample (FFPE slides) from archival tissue. The archival tissue can be an FFPE block or freshly cut slides derived from the initial diagnosis or recurrent setting within the previous 2 years. If archival tissue is not available, a fresh biopsy must be collected before C1D1. Details are provided in the Laboratory Manual.
• Have ECOG PS of 0 or 1 (see Section 8.4.4 for details).
• Have a life expectancy of ≥ 12 weeks.
• Have adequate organ and bone marrow function within 7 days before randomization/enrollment. For all parameters listed below, the most recent results available must be used to meet the inclusion criteria: See protocol 
• Have had an adequate treatment washout period before randomization/enrollment, defined as in the table below: See Protocol
• Agree not to enroll in another trial of an IMP, starting at the time of giving informed consent and continuously until the last planned visit in this trial.
• Are POCBP who have a negative serum beta-hCG pregnancy test. Women who are post-menopausal (defined as 12 months with no menses without an alternative medical cause) or permanently sterilized (verified by medical records) will not be considered POCBP and therefore are not required to undergo pregnancy testing.
• Are POCBP who agree to practice a highly effective form of contraception and to require their male partners to use condoms starting at the time of giving informed consent and continuously until 60 days or five half-lives of the IMP if known (whichever is longer) after receiving the last dose of IMP. For guidance on highly effective forms of contraception, see Section 10.5.2. 14 Are POCBP who agree not to donate eggs (ova, oocytes) for the purposes of assisted reproduction during trial, starting at the time of giving informed consent and continuously until 6 months after receiving the last dose of IMP.
• Are male who are sterile or if they are potentially fertile (i.e., are not surgically [e.g. have had a vasectomy] or congenitally sterile) and sexually active with a partner of childbearing potential, who agree to use condoms and to ask their female sexual partners to practice a highly effective form of contraception during the trial, starting at the time of giving informed consent and continuously until 6 months or five half-lives of the IMP if known (whichever is longer) after receiving the last dose of IMP. For guidance on highly effective forms of contraception, see Section 10.5.2.
• Are potentially fertile male who are willing to refrain from sperm donation, starting at the time of giving informed consent and continuously until 6 months after receiving the last dose of IMP.

Cohort-specific Inclusion Criteria:

• Have histologically or cytologically confirmed advanced (i.e., metastatic or locally recurrent where local therapy with curative intent is not possible) non-squamous and squamous NSCLC.
• Have documented absence of tumor activating, targetable EGFR mutations or ALK gene rearrangements.
• Have received at least one line of prior therapy for advanced disease, including either 1 line of PD-(L)1 inhibitor and/or platinum-based chemotherapy, either separately or combined (combined counts as 1 L of therapy), except if a participant is not a candidate for a platinum-based chemotherapy and/or PD1/PD-L1 inhibitor. Participants must present with progressive disease at trial enrollment.
• Have not received prior systemic therapy for metastatic NSCLC. Participants who received chemotherapy, radiotherapy, or chemoradiotherapy with curative intent for non-metastatic disease in the neoadjuvant or adjuvant setting are eligible for the trial if therapy was completed at least 6 months prior to initiation of trial treatment.
• Have histologically or cytologically confirmed SCLC with disease progression/relapse after first-line platinum‑based chemotherapy with or without immunotherapy.

Additional inclusion criteria for Part 2 Dose Optimization/Signal Seeking:

Cohort 1

• Have histologically or cytologically confirmed diagnosis of Stage IIIB or IIIC (who are not amenable to curative surgery or radiotherapy) or Stage IV nonsquamous NSCLC.
• Have documented absence of tumor activating, targetable EGFR mutations or ALK gene rearrangements.
• Have not received prior systemic therapy for metastatic NSCLC. Participants who received chemotherapy, radiotherapy, or chemoradiotherapy with curative intent for non-metastatic disease in the neoadjuvant or adjuvant setting are eligible for the trial if therapy was completed at least 6 months prior to initiation of trial treatment.

Cohort 2

• Have histologically or cytologically confirmed diagnosis of SCLC with disease progression/relapse after first-line platinum‑based chemotherapy with or without immunotherapy.

Cohort 3

• Have histologically or cytologically confirmed advanced or metastatic nonsquamous NSCLC.
• Have documented absence of tumor activating, targetable EGFR mutations or ALK gene rearrangements.
• Have received at least one line of prior therapy for advanced/metastatic disease, including either 1 line of PD-(L)1 inhibitor and/or platinum-based chemotherapy, either separately or combined (combined counts as one line of therapy), except if a participant is not a candidate for a platinum-based chemotherapy and/or PD1/PD-L1 inhibitor. Participants must present with progressive disease at trial enrollment.

Cohort 4

• Have histologically or cytologically confirmed diagnosis of Stage IIIB or IIIC (who are not amenable to curative surgery or radiotherapy) or Stage IV squamous NSCLC.
• Have documented absence of tumor activating, targetable EGFR mutations or ALK gene rearrangements.
• Have not received prior systemic therapy for metastatic NSCLC. Participants who received chemotherapy, radiotherapy, or chemoradiotherapy with curative intent for non-metastatic disease in the neoadjuvant or adjuvant setting are eligible for the trial if therapy was completed at least 6 months prior to initiation of trial treatment.

Cohort 5

• Have histologically or cytologically confirmed advanced squamous NSCLC.
• Have documented absence of tumor activating, targetable EGFR mutations or ALK gene rearrangements.
• Have received at least one line of prior therapy for advanced/metastatic disease, including either 1 line of PD-(L)1 inhibitor and/or platinum-based chemotherapy, either separately or combined (combined counts as 1 L of therapy), except if a participant is not a candidate for a platinum-based chemotherapy and/or PD1/PD-L1 inhibitor. Participants must present with progressive disease at trial enrollment.
• Documented disease progression during or following treatment for metastatic or locally advanced, inoperable NSCLC that included a platinum-containing regimen and a PD-1/PD-L1 checkpoint inhibitor, to a maximum of four previous lines of therapy.

Cohort 6

• NSCLC, non-squamous, AGA-positive, progressed on or recurred after at least one prior treatment with third generation TKI for EGFR-mutant disease, or progression on a 1st/2nd generation TKI with no detection of T790M mutation on progression.
• Have histologically or cytologically confirmed advanced or metastatic nonsquamous NSCLC.
• Documented positive test results for one or more driver mutation: EGFR, ALK, ROS1, MET, BRAF, RET, NTRK, HER2, KRAS, or other driver mutations with available targeted therapy.
• Have progressed on or recurred after at least one prior treatment with an EGFRmutant specific TKI, with no known detection of T790M mutation on progression.
• No prior chemotherapy for advanced/metastatic disease.
• NSCLC with documented disease progression during or following standard systemic treatment.

Cohort 7

• Have histologically or cytologically confirmed ES-SCLC.
• Have not received prior systemic therapy for metastatic disease.
• Participants with prior chemoradiotherapy for LS-SCLC are eligible if they have been treated with curative intent and had a treatment-free interval of at least 6 months since the last systemic anticancer treatment including chemotherapy, radiotherapy, or chemoradiotherapy before the diagnosis of ES-SCLC.
• Participants who have not received systemic therapy for ES-SCLC for various reasons including potential intolerance of the standard of care per the participant’s treating physician’s judgment are eligible.

Exclusion Criteria: 

• Prior treatment with B7-H3 targeted therapy.
• Prior treatment with ADC with topoisomerase inhibitor (e.g., trastuzumab deruxtecan).
• Is a candidate to locoregional treatment (including surgical resection, stereotactic radiotherapy or tumor ablation) with potential to induce complete or near complete response and prolonged tumor control (sometimes described as “radical” intent), per investigator’s assessment.
• Has a history of significant hematologic toxicity to prior lines of therapy, as assessed by investigator, e.g., Grade 4 febrile neutropenia or recurrent/persistent Grade 3 to 4 neutropenia.
• Have an uncontrolled concomitant or intercurrent illness, that in the opinion of the investigator, contra-indicates trial participation, limits compliance with trial procedures or substantially increases the risk of incurring AEs, including:
  • bleeding diathesis or active hemorrhage
  • active infection
  • Child-Pugh class B or C cirrhosis
  • pulmonary disease with significant impact in lung function
  • oncologic emergencies or complications (e.g. malignant hypercalcemia, superior vena cava syndrome, carcinoid syndrome that is unstable and with available alternative therapies)
  • psychiatric or abuse condition.
• Have uncontrolled or significant cardiovascular disease including any of the following:
  • Medical history of unstable angina, acute coronary syndrome, cerebral vascular accident or other Grade ≥ 3 cardiovascular events, within 6 months before randomization/enrollment or symptomatic chronic heart failure (New York Heart Association Class II to IV). Participants with troponin levels above ULN at screening and without any myocardial infarction related symptoms should have a cardiologic consultation before randomization/enrollment to rule out myocardial infarction.
  • Central or symptomatic peripheral pulmonary embolism within 3 months prior to randomization/enrollment. Participants with deep venous thrombosis and incidentally diagnosed peripheral pulmonary embolism are eligible if on a stable antithrombotic regimen.
  • Uncontrolled hypertension (defined as systolic BP ≥160 mm Hg and/or diastolic BP ≥100 mm Hg).
  • Uncontrolled and/or clinically important cardiac arrhythmias.
  • Fredericia’s formula-QT corrected interval QTcF prolongation to > 470 ms based on average of screening 12-lead ECG in triplicate.
  • Have LVEF < 50% by either ECHO or MUGA within 28 days before randomization/enrollment.
• Have clinically uncontrolled pleural effusion, ascites or pericardial effusion requiring drainage, peritoneal shunt, or cell-free concentrated ascites reinfusion therapy within 2 weeks prior to randomization/enrollment.
• Have a history of (non-infectious) ILD/pneumonitis that required steroids, have current ILD/pneumonitis, or where suspected ILD/pneumonitis cannot be ruled out by imaging at screening. Asymptomatic interstitial changes caused by previous radiotherapy, chemotherapy, or other factors such as smoking are acceptable.
• Have clinically active central nervous system metastases, defined as untreated and symptomatic, or requiring therapy with corticosteroids or anticonvulsants to control associated symptoms. Participants with treated brain metastases that are no longer symptomatic and who require no treatment with corticosteroids or anticonvulsants may be included in the trial if they have recovered from the acute toxic effect of radiotherapy. Participants with untreated, asymptomatic brain metastasis for whom local therapy is not indicated per standard of care may be eligible if neurologically stable per investigator’s assessment and (if deemed necessary by the investigator) after discussion with the sponsor’s medical monitor. Participants at imminent risk for spinal cord compression or leptomeningeal disease are not eligible.
• Participants who have a known history or a positive test at screening of any of the following:
  • HIV 1 or 2 infection.
  • Hepatitis B infection. If hepatitis B surface antigen and/or hepatitis B core antibody test results are positive, HBV DNA testing is required.
  • Have an active HCV infection; individuals who have completed curative antiviral treatment with HCV viral load below the limit of quantification are allowed. If the test for HCV antibody is positive, then HCV RNA should be tested.
• Have unresolved toxicities from previous anticancer therapy, defined as toxicities (other than alopecia) not yet resolved to Grade ≤ 1 or baseline. Toxicities that have resolved with sequelae (e.g. tracheostomy, chronic use of feeding tube, replacement hormones) are allowed, if not associated with increased risk of complications per investigator’s assessment.
• Are pregnant or breastfeeding or are planning pregnancy within 7 months after receiving last dose of BNT324 and within 6 months after last dose of BNT327, whichever is longer.
• Have a history of allergies, hypersensitivities, or intolerance to the trial treatments including any excipients thereof.
• Have a history of another primary malignancy within the previous 2 years, except adequately resected non-melanoma skin cancer, curatively treated in-situ disease, or other solid tumors curatively treated (adjuvant hormone therapy for malignancies at low risk of relapse is allowed) or have a known additional malignancy that is progressing or requires treatment.
• Use of any IMP within 28 days or five half-lives if known (whichever is longer) before administration of first dose of trial treatment or ongoing participation in the active treatment phase of another interventional clinical trial or prior randomization or treatment in a previous trial with the same IMPs as the current trial, regardless of treatment assignment.
• Have a medical, psychological, or social condition or substance abuse which, in the opinion of the investigator, could compromise their wellbeing if they participate in the trial, or that could prevent, limit, or confound the protocol-specified assessments or procedures, or that could impact adherence to protocol-described requirements.
• Are subject to exclusion periods from another investigational trial. 18 Are vulnerable individuals as per ICH E6 definition, i.e., are individuals whose willingness to volunteer in a clinical trial may be unduly influenced by the expectation, whether justified or not, of benefits associated with participation, or of a retaliatory response from senior members of a hierarchy in case of refusal to participate. This includes all sponsor, trial site, or third party (e.g., CRO, vendor) personnel directly involved in the conduct of the trial and their family members or dependents, as well as all trial site personnel otherwise supervised by the investigator.
• Have a history of small bowel obstruction requiring hospitalization within the past 3 months prior to the first dose of IMP.
• Have 24-h urine protein excretion ≥ 1 g. If qualitative urine protein is ≤ 1+, a 24-h urine protein quantitative test is not required.
• Have a history of Grade ≥ 3 irAEs that led to treatment discontinuation of a prior checkpoint inhibitor.
• Have active or a history of autoimmune disease (myasthenia gravis, myositis, autoimmune hepatitis, systemic lupus erythematosus, rheumatoid arthritis, psoriatic arthritis, inflammatory bowel disease, antiphospholipid antibody syndrome, Wegener granulomatosis, Sjögren’s syndrome, Guillain-Barré syndrome, or multiple sclerosis) with a risk of exacerbation following PD-L1 inhibition or have an immune deficiency (allogeneic hematopoietic stem cell transplantation or organ transplantation). Participants with the following conditions are eligible for the trial:
  • A history of autoimmune-related hypothyroidism and on thyroid replacement hormone.
  • Controlled Type 1 diabetes mellitus and on a stable insulin regimen.
  • Asthma that requires intermittent use of bronchodilators at no significant risk of clinically important exacerbation.
  • Eczema, psoriasis, lichen simplex chronicus, or vitiligo with dermatologic manifestations only provided all of following are true:
    • Rash covers <10% of body surface area.
    • Disease is well controlled at baseline and requires only lowpotency topical corticosteroids.

No occurrence of acute exacerbations of the underlying condition requiring psoralen plus ultraviolet A radiation, methotrexate, retinoids, biologic agents, oral calcineurin inhibitors, or high potency or oral corticosteroids within the previous 12 months.

• Have serious non-healing wounds, ulcers, or bone fractures. This includes history of abdominal fistula, gastrointestinal perforation, or intra-abdominal abscess for which an interval of 6 months must pass before enrollment into this trial. In addition, the participant must have undergone correction (or spontaneous healing) of the perforation/fistula and/or the underlying process causing the fistula/perforation.
• Have evidence of major coagulation disorders or other significant risks of hemorrhage such as:
  • history of intracranial or intraspinal hemorrhage
  • tumor lesions invading large vessels and with significant risk of bleeding
  • thrombosis or embolism, or significant vascular disease (such as aortic aneurysm requiring surgery) within 6 months prior to the first dose of IMP
  • clinically significant hemoptysis or tumor hemorrhage within 1 month prior to the first dose of IMP
  • anticoagulant therapy for therapeutic purposes (except low molecular weight heparin) within 14 days prior to the first dose of IMP
  • received antiplatelet drugs including, but not limited to, aspirin (> 100 mg/day), clopidogrel (> 75 mg/day), dipyridamole, ticlopidine, cilostazol or any herbal or folk medicines know to be associated with increased bleeding risks, within 10 days prior to the initiation of trial treatment
  • received prior treatment with a PD(L)-1/VEGF bispecific antibody.
• Active ILD/pneumonitis or a history of ILD/pneumonitis requiring treatment with systemic steroids or other immunosuppressive treatment.

Note: Other protocol defined Inclusion/Exclusion Criteria may apply.

Eligibility last updated 3/7/2025. Questions regarding updates should be directed to the study team contact.