In this study researchers are testing Risvutatug rezetecan also known as (Ris-Rez) a new medicine that targets specific proteins (B7-H3) on cancer cells, thereby reducing the cancer's ability to grow and spread. This study specifically aims to evaluate how well Ris-Rez works in treating relapsed SCLC compared to standard treatment topotecan, by checking whether Ris-Rez makes cancers smaller or disappear completely and if it helps participants live longer. The study is also assessing whether Ris-Rez is safe and tolerated well by participants compared to topotecan and provide a better understanding of the main side effects of both drugs. Participants with relapsed SCLC will be randomly divided into two groups: one group receiving Ris-Rez and the other receiving topotecan.

Inclusion Criteria:

Participants are eligible to be included in the study only if all of the following criteria apply:

• Adults >18 or the minimum legal adult age at the time the informed consent form is signed
• Has histologically or cytologically confirmed extensive-stage small cell lung cancer (ES-SCLC).
• Has received 1 prior platinum-based systemic therapy with a PD- (L)1 inhibitor for at least 2 cycles of therapy and a chemotherapy free-interval of >30 days, with documented progression. Participants with prior tarlatamab treatment in either the first- or second-line ES-SCLC setting are eligible.
• Has at least 1 target lesion per RECIST 1.1, as determined by the investigator.
• Is capable of giving signed informed consent, including compliance with the requirements and restrictions listed in the ICF and in the protocol.
• Has adequate organ function and an ECOG performance status of 0 or 1

Exclusion Criteria:

Participants are excluded from the study if any of the following criteria apply:

• Pathological diagnosis of complex SCLC or transformed SCLC.
• Limited stage small cell lung cancer at diagnosis
• Has received any prior therapy with an Antibody-drug conjugate (ADC) with a Topoisomerase-1 (TOPO1)-inhibitor payload or treatments targeting B7-H3.
• Has known sensitivity to study intervention components or excipients or other allergy that, in the opinion of the investigator or medical monitor, contraindicates participation in the study.
• Has severe, uncontrolled or active cardiovascular disorders.
• Has clinically significant bleeding symptoms or significant bleeding tendency within 1 month prior to the first dose.
• Known active infectious diseases requiring systemic treatment or known Human immunodeficiency virus (HIV).
• Has symptomatic brain metastases or untreated progression exclusively due to brain metastasis during or after the last treatment prior to screening, evidence of leptomeningeal/meningeal/brainstem metastasis or evidence of spinal cord metastases.
• Has any evidence of current interstitial lung disease or pneumonitis or a prior history of ILD or non-infectious pneumonitis requiring high dose steroids.
• Has significant pulmonary disease or respiratory impairment (e.g., uncontrolled asthma/COPD, restrictive lung disease),
• Has active Hepatitis B or Hepatitis C

Study Sponsor will assess requests from qualified researchers for anonymized individual patient-level data and related study documents. Data sharing is subject to certain criteria, conditions, and exceptions. For further information, refer to https://www.gsk-studyregister.com/gsk-patient-level-data-sharing-july2025.pdf

Anonymized IPD will be made available within 6 months of publication of primary, key secondary and safety results for studies in product with approved indication(s) or asset(s) with development terminated across all indications.

Anonymized IPD is shared with researchers whose proposals are approved by an Independent Review Panel and after a Data Sharing Agreement is in place. Access is provided for an initial period of 12 months, but an extension may be granted, when justified, for up to 6 months.