A Study to Evaluate Enfortumab Vedotin (EV) in Participants With Previously Treated Locally Advanced or Metastatic Malignant Solid Tumors

• Histologically or cytologically confirmed HR+/HER2- breast cancer, TNBC, squamous or non-squamous NSCLC, head and neck cancer; gastric, GEJ, or esophageal cancer
• Evidence of progression on or after the last regimen received
• Locally advanced or metastatic disease not amenable to curative intent treatment
• Accessible archival tumor tissue from either the primary tumor or a metastatic site
• Measurable disease by RECIST Version 1.1
• ECOG PS of 0 or 1
• Participant is considered an adult according to local regulation at the time of signing the informed consent form (ICF)
• Participant has the following baseline laboratory data. If a participant has received a recent blood transfusion, the hematology tests must be obtained ≥28 days after any blood transfusion
  • absolute neutrophil count (ANC) ≥1.0 × 10⁹/L
  • platelet count ≥100 × 10⁹/L
  • hemoglobin ≥9 g/dL
  • serum total bilirubin ≤1.5 × upper limit of normal (ULN) or ≤3 × ULN for participants with Gilbert’s disease
  • creatinine clearance (CrCl) ≥30 mL/min as estimated per institutional standards or as measured by 24-hour urine collection (glomerular filtration rate GFR can also be used instead of CrCl)
  • alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤3 × ULN
• Participant agrees not to participate in another interventional study while receiving study treatment in the present study
• Additional contraceptive requirements exist for male and female participants

Cohort 1: HR+/HER2- breast cancer:

• Participant has histologically or cytologically confirmed HR+/HER2- (estrogen receptor [ER] positive and/or progesterone receptor [PR] positive, and HER2 negative) breast cancer and is not considered a candidate for further hormonal therapy. Participant will be considered HR+ if biopsies show ≥1% expression of ER or PR as per current American Society of Clinical Oncology/College of American Pathologists (ASCO/CAP) guidelines
• Participant must have received a taxane or anthracycline in the neoadjuvant, adjuvant, or incurable locally advanced or metastatic setting
  • Prior cytotoxic regimen received in the neoadjuvant or adjuvant setting will count as a prior cytotoxic regimen if disease recurrence occurred during or within 6 months of completing the regimen
• Participant has progressed, relapsed, or discontinued for toxicity during or after at least 1 prior standard of care cytotoxic regimen in the incurable, unresectable, locally advanced, or metastatic setting, and has not received >2 prior lines of cytotoxic therapy in the locally advanced or metastatic setting. No limit applies to endocrine therapies. Poly (ADP-ribose) polymerases (PARP) inhibitors do not count as a line of cytotoxic therapy
• Participant has progressed, relapsed, or discontinued for toxicity during or after receiving endocrine therapy or with hormonally directed therapy with cyclin-dependent kinase (CDK) inhibitors. Prior therapy with CDK inhibitors is not required

Cohort 2: triple-negative breast cancer (TNBC):

• Participant has histologically or cytologically confirmed TNBC, defined as unequivocal TNBC histology (ER-negative/PR-negative/HER2-negative). This is defined by <1% expression of ER and PR by immunohistochemistry (IHC), and that are, for HER2, either 0 to 1+ by IHC, or IHC 2+ and fluorescence in situ hybridization (FISH) negative (not amplified) as per current ASCO/CAP guidelines
• Participant must have received a taxane or anthracycline in the neoadjuvant, adjuvant, or incurable locally advanced or metastatic setting
  • Prior cytotoxic regimen received in the neoadjuvant or adjuvant setting will count as a prior cytotoxic regimen if disease recurrence occurred during or within 6 months of completing the regimen
• Participant has progressed, relapsed, or discontinued for toxicity during or after at least 1 prior standard of care cytotoxic regimen in the incurable, unresectable, locally advanced, or metastatic setting, and has not received >2 prior lines of cytotoxic therapy in the locally advanced or metastatic setting. Poly (ADP-ribose) polymerases (PARP) inhibitors do not count as a line of cytotoxic therapy
• Participant has received prior therapy with an anti-programmed cell death protein-1 (PD-1) or an anti-programmed cell death-ligand 1 (PD-L1) based on participant’s tumor PD-1 or PD-L1 expression and local treatment guidelines and has progressed or discontinued treatment due to toxicity, or therapy is contraindicated for participant

Cohort 3: squamous non-small cell lung cancer (NSCLC):

• Participant has histologically or cytologically confirmed squamous NSCLC
  • Participants with mixed-histology NSCLC are eligible provided there is not any component of neuroendocrine histology
  • Participants with known epidermal growth factor receptor (EGFR), anaplastic lymphoma kinase (ALK), reactive oxygen species (ROS), BRAF, or other actionable mutations are eligible if treated with mutation-targeted therapy and have progressed, relapsed, or discontinued treatment due to toxicity
• Participant has progressed, relapsed, or discontinued treatment due to toxicity after 1 platinum-based standard of care regimen for locally advanced or metastatic disease, and has not received >2 prior lines of cytotoxic anticancer therapy in the locally advanced or metastatic setting
  1. Participants with locally advanced disease who previously received curative intent treatment with platinum-based standard of care regimen in the adjuvant or neoadjuvant setting or as part of concomitant chemoradiation therapy are eligible if they have progressed or relapsed within 6 months of completion.
  2. Maintenance therapy does not constitute a new chemotherapy regimen provided there was no progression after the initial platinum-based regimen.
  3. Changing chemotherapy agents during platinum-based treatment for the management of toxicities does not constitute a new chemotherapy regimen provided no progression had occurred while on the initial therapy.
• Participant has received prior therapy with an anti-programmed cell death protein-1 (PD-1) or anti-programmed cell death-ligand 1 (PD-L1) based on participant’s tumor PD-1 or PD-L1 expression and local treatment guidelines and has progressed, relapsed, or discontinued treatment due to toxicity, or therapy is contraindicated for participant

Cohort 4: non-squamous non-small cell lung cancer:

• Participant has histologically or cytologically confirmed non-squamous NSCLC
  • Participants with mixed-histology NSCLC are eligible provided there is not any component of neuroendocrine histology
  • Participants with known EGFR, ALK, ROS, BRAF, or other actionable mutations are eligible if treated with mutation targeted therapy and have progressed, relapsed, or discontinued treatment due to toxicity
• Participant has progressed, relapsed, or discontinued treatment due to toxicity after 1 platinum-based standard of care regimen for locally advanced or metastatic disease, and has not received >2 prior lines of cytotoxic anticancer therapy in the locally advanced or metastatic setting
  1. Participants with locally advanced disease who previously received curative intent treatment with platinum-based standard of care regimen in the adjuvant or neoadjuvant setting or as part of concomitant chemoradiation therapy are eligible if they have progressed or relapsed within 6 months of completion.
  2. Maintenance therapy does not constitute a new chemotherapy regimen provided there was no progression after the initial platinum-based regimen.
  3. Changing chemotherapy agents during platinum-based treatment for the management of toxicities does not constitute a new chemotherapy regimen provided no progression has occurred while on the initial therapy.
• Participant has received prior therapy with an anti–PD-1 or anti–PD-L1 based on participant’s tumor PD-1 or PD-L1 expression and local treatment guidelines and has progressed, relapsed, or discontinued treatment due to toxicity, or therapy is contraindicated for participant

Cohort 5: head and neck cancer:

• Participant has histologically or cytologically confirmed head and neck cancer
  • Primary tumor site must arise from the oral cavity, oropharynx, hypopharynx, and larynx; tumors arising from the nasopharynx are excluded. Salivary gland tumors and/or parotid gland tumors are not eligible for Cohort 5
• Participant has progressed, relapsed, or discontinued treatment due to toxicity after 1 platinum-based standard of care regimen for locally advanced or metastatic disease, and has not received >2 prior lines of cytotoxic anticancer therapy in the locally advanced or metastatic setting
  • Participants with locally advanced disease who previously received curative intent treatment with platinum-based standard of care regimen in the adjuvant or neoadjuvant setting or as part of concomitant chemoradiation therapy are eligible if they have progressed or relapsed within 6 months after completion
• Participant has received prior therapy with an anti–PD-1 or anti–PD-L1 based on participant’s tumor PD-1 or PD-L1 expression and local treatment guidelines and has progressed, relapsed, or discontinued treatment due to toxicity, or therapy is contraindicated for participant

Cohorts 6, 7, and 8: gastric or gastroesophageal junction (GEJ) or esophageal adenocarcinoma:

• Participant has histologically or cytologically confirmed gastric, GEJ, or esophageal cancer
• Participant has progressed, relapsed, or discontinued due to toxicity after 1 platinum-based standard of care regimen for locally advanced or metastatic disease, and has not received >2 prior lines of cytotoxic anticancer therapy in the locally advanced or metastatic setting
  • Neoadjuvant or adjuvant cytotoxic regimens will count as a prior regimen if relapsed or progressed ≤6 months after completion
• Participant must have received a HER2-directed therapy if known to have HER2-positive cancer
• Participant has received prior therapy with an anti–PD-1 or anti–PD-L1 based on participant’s tumor PD-1 or PD-L1 expression and local treatment guidelines and has progressed, relapsed, or discontinued treatment due to toxicity, or therapy is contraindicated for participant

• Participant has preexisting sensory or motor neuropathy Grade ≥2
• Participant has active central nervous system (CNS) metastases. Participants with treated CNS metastases are permitted on study if all the following are true:
  • CNS metastases have been clinically stable for ≥6 weeks prior to screening
  • If requiring steroid treatment for CNS metastases, the participant is on a stable dose ≤20 mg/day of prednisone or equivalent for ≥2 weeks
  • Baseline imaging scans show no evidence of new or enlarged brain metastasis
  • Participant does not have leptomeningeal disease
• Participant has ongoing clinically significant toxicity (Grade 2 or higher with the exception of alopecia) associated with prior treatment (including systemic therapy, radiotherapy, or surgery)
• Participants with ongoing ≥Grade 3 immunotherapy-related hypothyroidism or panhypopituitarism are excluded. Participants with ongoing immunotherapy-related colitis, uveitis, myocarditis, or pneumonitis, or participants with other immunotherapy-related AEs requiring high doses of steroids (>20 mg/day of prednisone or equivalent), are excluded. Participant with ≤Grade 2 immunotherapy-related hypothyroidism or panhypopituitarism may be enrolled when well-maintained/controlled on a stable dose of hormone replacement therapy (if indicated)
• Participant has a history of uncontrolled diabetes mellitus within 3 months before the first dose of study treatment. Uncontrolled diabetes (within 3 months before first dose) is defined as hemoglobin A1c (HbA1c) ≥8% or HbA1c between 7 and <8% with associated diabetes symptoms (polyuria or polydipsia) that are not otherwise explained. The lowest HbA1c during the screening period will be used to determine eligibility
• Participant has prior treatment with EV or other monomethyl auristatin E (MMAE) based antibody-drug conjugates (ADCs)
• Participant has a second malignancy diagnosed within 3 years before first dose of study drug, or any evidence of residual disease from a previously diagnosed malignancy. Participants with non-melanoma skin cancer, localized prostate cancer treated with curative intent with no evidence of progression, low-risk or very low-risk (per standard guidelines) localized prostate cancer under active surveillance/watchful waiting without intent to treat, or carcinoma in situ of any type (if complete resection was performed) are allowed
• Participant is currently receiving systemic antimicrobial treatment for viral, bacterial, or fungal infection at the time of first dose of study treatment. Routine antimicrobial prophylaxis is permitted
• Participant has known active hepatitis B (eg, hepatitis B surface antigen HBsAg reactive) or active hepatitis C (eg, hepatitis C virus HCV RNA qualitative is detected)
• Participant has known history of human immunodeficiency virus (HIV) infection (HIV 1 or 2)
• Participant has documented history of a cerebrovascular event (stroke or transient ischemic attack), unstable angina, myocardial infarction, or cardiac symptoms (including congestive heart failure) consistent with New York Heart Association Class III-IV within 6 months prior to the first dose of study drug
• Participant has major surgery within 4 weeks prior to first dose of study drug
• Participant had radiotherapy, chemotherapy, biologics, investigational agents, and/or antitumor treatment with immunotherapy that is not completed 2 weeks prior to first dose of study drug
• Participant has known hypersensitivity to EV or to any excipient contained in the drug formulation of EV (including histidine, trehalose dihydrate, and polysorbate 20) OR participant has known hypersensitivity to biopharmaceutical produced in Chinese hamster ovary cells
• Participant has known active keratitis or corneal ulcerations. Participant with superficial punctate keratitis is allowed if the disorder is being adequately treated
• Participant has any condition which makes the participant unsuitable for study participation