A Clinical Trial to Test if an Investigational Combination Therapy With BNT326 and BNT327 is Safe and Potentially Beneficial for People With Advanced Non-small Cell Lung Cancer (NSCLC)

Key Inclusion Criteria (applicable to all participants and all parts unless otherwise specified):

* Aged ≥18 years at the time of giving informed consent. Local laws will be followed if the age of consent is older.
* Have measurable disease defined by RECIST v1.1.
* Have Eastern Cooperative Oncology Group performance status of 0 or 1.
* Have adequate organ and bone marrow function within 7 days before randomization/enrollment as defined in the protocol.
* Have advanced (i.e., metastatic or locally recurrent where local therapy with curative intent is not possible) non-squamous or squamous NSCLC.

Cohort-specific inclusion criteria

Part 1, 2L+, squamous or non-squamous NSCLC, AGA-negative/positive, any PD-L1 (NOTE: regimens used as neoadjuvant and/or adjuvant treatment may be considered as prior lines for advanced disease if relapse occurred within 6 months of the last dose.)

* for AGA-negative NSCLC only:

  * Have no actionable genomic alterations, such as EGFR mutations, anaplastic lymphoma kinase (ALK) gene rearrangements, or other genomic alterations for which targeted molecular therapies are available.
  * Have experienced relapse or progression during or after treatment with standard systemic therapy in the advanced/metastatic setting or discontinued from prior therapy due to intolerance.
  * Participants must have received 1 to 3 lines of systemic treatment in the metastatic setting, which can include anti-PD-1/PD-L1 therapy, chemotherapy, and anti-angiogenic agents. These treatments may be administered concurrently or sequentially. However, prior chemotherapy treatment must be limited to 2 lines or less.
* for AGA-positive NSCLC only (excluding EGFR activating mutation):

  * Have documented positive test results for one or more actionable genomic alteration: EGFR (other than activating mutations), ALK, ROS proto-oncogene 1 (ROS1), gene encoding the hepatocyte growth factor receptor (MET), human gene that encodes a protein called B-Raf (BRAF), rearranged during transfection (RET), neurotrophic tropomyosin-receptor kinase (NTRK), human epidermal growth factor receptor 2 (HER2), Kirsten rat sarcoma virus (KRAS), or other genomic alteration with available targeted therapy.
  * Must have received at least one prior systemic therapy for advanced disease, which must have included targeted treatment for actionable genomic alterations, which include alterations such as EGFR (other than activating mutations), ALK, ROS1, MET, BRAF, RET, NTRK, HER2, KRAS, or other alterations for which targeted therapies are available as a part of local SoC.
  * Participants may have received between 1 to 3 lines of systemic treatment of anti-PD-1/PD-L1 therapy, chemotherapy, and/or anti-angiogenic agents. These treatments may be administered concurrently (including with tyrosine kinase inhibitor \[TKI\]) or sequentially. However, chemotherapy treatment must be limited to 2 lines or less.
  * Have experienced progression during or after treatment or discontinued from prior therapy due to intolerance.
* for AGA-positive NSCLC only (with EGFR activating mutation):

  * Have documented positive test results for an EGFR-sensitizing mutation (EGFR-sensitizing mutation Exon 21-L858R and 19del).
  * Participants must have received one or two prior lines of systemic therapy for advanced and/or metastatic disease, which must include treatment with an approved EGFR TKI, with at least one being a third-generation EGFR TKI.
  * Participants receiving an EGFR TKI at the time of signing informed consent may continue to take the EGFR TKI until 5 days prior to Cycle 1 Day 1.
  * Chemotherapy is permitted only if it was administered in combination with an EGFR TKI as part of a single line of therapy and as the initial (first line) treatment for advanced/metastatic disease.
  * Have experienced progression during or after treatment or discontinued from prior therapy due to intolerance.

Part 2a (Cohort A), 2L+, squamous or non-squamous NSCLC, AGA-negative/positive, any PD-L1 (NOTE: regimens used as neoadjuvant and/or adjuvant treatment may be considered as prior lines for advanced disease if relapse occurred within 6 months of the last dose.)

* for AGA-positive NSCLC only, excluding EGFR activating mutation:

  * Have documented positive test results for one or more actionable genomic alterations: EGFR (other than activating mutations), ALK, ROS1, MET, BRAF, RET, NTRK, HER2, KRAS, or other genomic alterations, with available targeted therapy.
  * May have received 1 to 4 lines of systemic treatment, of which one prior systemic therapy for advanced disease must have included targeted treatment for actionable genomic alterations, which include alterations such as EGFR (other than activating mutations), ALK, ROS1, MET, BRAF, RET, NTRK, HER2, KRAS, or other genomic alterations for which targeted therapies are available as part of local SoC.
  * Other therapies may include anti-PD-1/PD-L1 therapy, chemotherapy, and anti-angiogenic agents. These treatments may be administered concurrently/in combination (including with TKI) or sequentially. However, chemotherapy treatment must be limited to 2 lines or less.
  * Have experienced progression during or after treatment or discontinued from prior therapy due to intolerance.
* for AGA-positive NSCLC only, with EGFR activation mutation:

  * Have documented positive test results for an EGFR-sensitizing mutation (EGFR-sensitizing mutation Exon 21-L858R and 19del).
  * Participants must have received one or two prior lines of systemic therapy for advanced and/or metastatic disease, which must include treatment with an approved EGFR TKI, with at least one being a third-generation EGFR TKI.
  * Participants receiving an EGFR TKI at the time of signing informed consent may continue to take the EGFR TKI until 5 days prior to Cycle 1 Day 1.
  * Chemotherapy is permitted only if it was administered in combination with an EGFR TKI as part of a single line of therapy and as the initial (first line) treatment for advanced/metastatic disease.
  * Have experienced progression during or after treatment or discontinued from prior therapy due to intolerance.

Part 2a (Cohort B), 1L, squamous or non-squamous NSCLC, AGA-negative, any PD-L1

* Have no actionable genomic alterations, such as EGFR mutations, ALK rearrangements, or other genomic alterations for which targeted molecular therapies are available.
* Have received no systemic anti-cancer treatment in the advanced/metastatic setting. May have received neoadjuvant and/or adjuvant treatment if progression to advanced/metastatic disease occurred at least 6 months after completing such therapy and have not received treatment in the advanced/metastatic setting.

Part 2b (Cohort C), 2L+, squamous or non-squamous NSCLC, AGA-negative or EGFR activating mutation, any PD-L1

* for AGA-negative NSCLC only:

  * Have no actionable genomic alterations, such as EGFR mutations, ALK rearrangements, or other genomic alterations for which targeted molecular therapies are available.
  * Participants should have received 1 to 4 lines of systemic treatment, which can include anti-PD-1/PD-L1 therapy, chemotherapy, and/or anti-angiogenic agents.
  * Regimens used as neoadjuvant and/or adjuvant treatment may be considered as prior lines for advanced disease if relapse occurred within 6 months of the last dose.
* for EGFR-sensitizing mutation NSCLC only:

  * Have documented positive test results for an EGFR-sensitizing mutation (EGFR-sensitizing mutation Exon 21-L858R and 19del).
  * Have received 1 or 2 prior systemic therapies for advanced and/or metastatic disease with an approved EGFR TKI, which must include one third-generation anti-EGFR TKI.
  * Participants receiving an EGFR TKI at the time of signing informed consent may continue to take the EGFR TKI until 5 days prior to Cycle 1 Day 1.
  * Chemotherapy is permitted only if it was administered in combination with an EGFR TKI as part of a single line of therapy and as the initial (first line) treatment for advanced/metastatic disease.
  * May have received neoadjuvant and/or adjuvant treatment if progression to advanced/metastatic disease occurred at least 6 months after completing such therapy and have experienced disease progression on or after EGFR TKI treatment administered in the advanced/metastatic setting.
  * Have experienced progression during or after treatment or discontinued from prior therapy due to intolerance.

Part 2b (Cohort D1) 1L, squamous or non-squamous NSCLC, AGA-negative, PD-L1 ≥50% and Part 2b (Cohort D2) 1L, squamous or non-squamous NSCLC, AGA-negative, PD-L1 \<50%

* Have no actionable genomic alterations, such as EGFR mutations (Cohort D1)/EGFR-sensitizing mutations (Cohort D2), ALK rearrangements, or other genomic alterations for which targeted molecular therapies are available.
* Have not received prior systemic therapy for advanced and/or metastatic disease. May have received neoadjuvant and/or adjuvant treatment if progression to advanced/metastatic disease occurred at least 6 months after completing such therapy and have not received treatment in the advanced/metastatic setting.

Key Exclusion Criteria (applicable to all participants and all parts):

* Had disease progression on or were intolerant to prior treatment with an agent targeting HER3 (including antibody, ADC, cell therapy, and other drugs) or with a topoisomerase I inhibitor payload (including topoisomerase I inhibitor-containing ADCs). Note: For Part 2a Cohort A, prior exposure to agents targeting HER3 or topoisomerase I inhibitor payload may be allowed on a case-by-case basis after discussion with and approval by the sponsor.
* Have an uncontrolled concomitant or intercurrent illness, that contra-indicates study participation, limits compliance with study procedures or substantially increases the risk of incurring AEs, including:

  * Bleeding diathesis or active hemorrhage
  * Clinically significant active infection, including respiratory viral infection
  * Child-Pugh class B or C cirrhosis
  * Known pulmonary disease with significant impact in lung function and/or with potential risk of severe infection
  * 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
  * Infectious colitis Grade ≥2 not resolved to Grade 1 within 72 h within the past 3 months
* Have left ventricular ejection fraction \<50% by either echocardiography or multi-gated acquisition (scanning) 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) interstitial lung disease (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 radiation therapy, chemotherapy, or other factors such as smoking are acceptable.
* Have had exposure to protocol-specific treatments with a washout period before randomization/enrollment.
* Have clinically active central nervous system metastases, defined as untreated and symptomatic, or requiring therapy with corticosteroids or anticonvulsants to control associated symptoms.
* Are participants of childbearing potential who are pregnant or breastfeeding or are planning pregnancy within the time specified in the protocol or are potentially fertile males, who are planning to father children during the study or within the time specified in the protocol.
* Are subject to exclusion periods from another investigational study.
* Have a history of small bowel obstruction requiring hospitalization within the past 3 months prior to the first dose of IMP.
* Have urine protein ≥2+ and 24-hour urine protein excretion ≥1 g. If qualitative urine protein is ≤1+, a 24-hour urine protein quantitative test is not required.
* Have a history of Grade ≥3 immune-related adverse events that led to treatment discontinuation of a prior checkpoint inhibitor.
* Have a significant risk of hemorrhage (per investigator clinical judgment) indicated by protocol defined criteria.
* Have active or chronic clinically significant corneal disorders or any clinically significant corneal disease that prevents adequate monitoring of drug-induced keratopathy.

NOTE: Other protocol defined Inclusion/Exclusion criteria apply.