The goal of this study is to assess the safety, tolerability, clinical activity and pharmacokinetics of Risvutatug rezetecan (Ris-Rez), also known as GSK5764227. The study will also see how the levels of Ris-Rez will change over time at different dose amounts when administered alone and in combination with other medicines like carboplatin, cisplatin, atezolizumab, pembrolizumab, durvalumab, bevacizumab, cetuximab, tarlatamab, dostarlimab

Inclusion criteria

• Male or female participants at least 18 years of age (≥18 years)
• Participants with histologically confirmed advanced/metastatic solid tumors, as defined per study phase and cohort, as follows:

Phase 1a:

1. Participants with advanced/metastatic solid tumors.

2. For monotherapy dose escalation: participants must have progressed on or become intolerant to all available SOC therapies.

3. For combination dose escalation: participants must have received 3 or fewer prior lines of systemic anticancer therapy in the advanced/metastatic setting

   • Has at least 1 target lesion per RECIST 1.1, as determined by the investigator.
   • Has an ECOG performance status of 0 or 1, with no deterioration in the 2 weeks before first dose.
   • Has adequate organ function.
   • Where available, participants should provide a formalin fixed and paraffin embedded (FFPE) tumor sample from the most recent biopsy of primary cancer or from a metastatic site for central testing.

Exclusion criteria

• Has ongoing adverse reaction(s) from prior therapy that has(have) not recovered to ≤Grade 1 or to the baseline status preceding prior therapy.

• Prior treatment with orlotamab, enoblituzumab, I-Dxd, or other B7-H3 targeted agents.

• Primary brain tumor or evidence of brain metastasis (unless meeting the following criteria at the same time: asymptomatic; medically stable for at least 4 weeks prior to initial dosing; no steroid treatment required for at least 4 weeks prior to initial dosing; and no midline shift due to herniation); or untreated progression due to brain metastasis or primary brain tumor during or after the last treatment prior to screening; or evidence of meningeal/brainstem involvement; or evidence of spinal cord compression (detected by radiographic examination, symptomatic or not).

• Any of the following cardiac examination abnormality:

  1. Has QT interval, corrected for heart rate (QTc) >450 msec or QTc >480 msec for participants with bundle branch block.
  2. Evidence of current clinically significant arrhythmias or ECG abnormalities (e.g., complete left bundle branch block, third-degree atrioventricular [AV] block, second-degree AV block, PR interval >250 msec).
  3. Risk factors of prolonged QTc or arrhythmia events, such as heart failure, refractory hypokalemia, congenital long QT syndrome, family history of long QT syndrome, or unexplained sudden death of any direct relative under 40 years old or any concomitant medications that prolong the QT interval.
  4. Left ventricular ejection fraction (LVEF) <50%.

• Has severe, uncontrolled or active CV disorders, serious or poorly controlled hypertension, clinically significant bleeding symptoms or serious arteriovenous thromboembolic events

• Participants with evidence of current ILD/non-infectious pneumonitis OR a prior history of ILD/non-infectious pneumonitis requiring high-dose glucocorticoids OR suspected ILD/non-infectious pneumonitis that cannot be ruled out by imaging.

• Has a history of autoimmune disease that has required systemic treatments in the 2 years prior to screening. Participants with prior history of autoimmune disease must be discussed with the medical monitor. Replacement therapy is not considered a form of systemic therapy (e.g., thyroid hormone for autoimmune thyroiditis or insulin is not exclusionary).

• Has any history of prior allogenic or autologous bone marrow transplant or other solid organ transplant.

• Has received prior anticancer therapy within 28 days of the first dose of study intervention or having to continue these medications during the study.