A randomized, phase 3, open-label study to evaluate PF-08046054/SGN-PDL1V versus docetaxel in adult participants with previously treated programmed cell death ligand 1 (PD-L1) positive non-small-cell lung cancer (NSCLC)

Study intervention refers to PF-08046054 and Docetaxel.

PF-08046054/SGN-PDL1V, which will be referred to as PF-0804605 is an ADC that targets PD-L1, a member of the B7 family of immune checkpoint molecules. PF-08046054 is comprised of an average of 4 molecules of MMAE conjugated to native cysteines of the PD-L1 targeting, effector function null antibody SG55901 LALA using the maleimidocaproyl vc linker system (vcMMAE/vedotin)
(Doronina et al. 2003). This druglinker and conjugation methodology have been clinically validated in other approved therapeutics including brentuximab vedotin, enfortumab vedotin, and polatuzumab vedotin (Senter and Sievers 2012; Rosenberg et al. 2019; Tilly et al. 2019).
PF-08046054 is designed to bind to PD-L1 on the cell surface, internalize and traffic intracellularly through the endo-lysosomal pathway, and cause subsequent mitotic arrest an apoptotic tumor cell death through released MMAE.

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• Histologically or cytologically confirmed diagnosis of locally advanced, unresectable Stage IIIB and IIIC not eligible for definitive chemoradiotherapy or metastatic (Stage IV: M1a, M1b, or M1c) NSCLC per the AJCC Staging Manual, Version 8.0, and the UICC Staging System. Note: Participants with a neuroendocrine component or histology are not eligible.

• PD-[L]1 expression on ≥1% of tumor cells based on local IHC testing with an assay utilizing the anti-PD-L1 monoclonal antibody clones 22C3 or SP263.

• Participants who have NSCLC with known AGAs are permitted (eg, EGFR mutations, ALK translocations).

• Participants must have received the following therapies and progressed during or relapsed after receiving their most recent prior therapy

• Participants with no known AGAs must fulfill 1 of the following conditions:

  • Received a platinum-based combination therapy for the treatment of metastatic or recurrent disease and a PD-[L]1 monoclonal antibody (concurrently or sequentially with platinum-based chemotherapy), unless contraindicated.
  • Experienced disease progression within 6 months of the last dose of platinum-based chemotherapy in the adjuvant, neoadjuvant, or chemoradiotherapy setting and received a PD-[L]1 monoclonal antibody at any time during the course of treatment.

• Participants with known AGAs (eg, EGFR mutations, ALK translocations, or other relevant actionable mutations) must fulfill the following conditions:

  • Must have received at least 1 approved AGA-targeted therapy and, in the opinion of the investigator, additional AGA-targeted therapy is not in the best interest of the participant
  • Received a platinum-based combination therapy for the treatment of metastatic or recurrent disease, or experienced disease progression within 6 months of the last dose of platinum-based chemotherapy in the adjuvant, neoadjuvant, or chemoradiotherapy setting.
  • May have received PD-[L]1 monoclonal antibody (concurrently or sequentially with platinum-based chemotherapy).

• Able to provide any of the following tumor tissues for biomarker analysis:

  • Archival specimen (preferably collected within 12 months after the last anticancer therapy) (see laboratory manual for details); or
  • Fresh tissue from a tumor lesion, if medically feasible.

• Adequate organ function obtained within 7 days prior to study intervention initiation

See protocol for full version:

• History of another malignancy within 3 years before the first dose of study intervention, or any evidence of residual disease from a previously diagnosed malignancy. Exceptions are malignancies with a negligible risk of metastasis or death (eg, 5-year overall survival [OS] ≥90%), such as adequately-treated carcinoma in situ of the cervix, non-melanoma skin carcinoma, localized prostate cancer, ductal carcinoma in situ, or Stage I uterine cancer
• Active central nervous system (CNS) lesions, are excluded. Active is defined as untreated or symptomatic requiring corticosteroids >10mg/day of prednisone equivalent within the previous 14 days.
• Participants with a history of leptomeningeal metastasis are excluded.
• Pre-existing neuropathy ≥Grade 2 per NCI CTCAE v5.0.
• Active viral, bacterial, or fungal infection of any grade (per the NCI CTCAE, Version 5.0) within 2 weeks prior to the first dose of study intervention, unless deemed not clinically significant by the investigator (eg, onychomycosis).
  Routine antimicrobial prophylaxis is permitted.
• Has an active autoimmune disease that has required systemic treatment in past 2 years (ie, with use of disease modifying agents, corticosteroids or immunosuppressive drugs). Replacement therapy (eg, thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency) is not considered a form of systemic treatment and is allowed.
• Has a diagnosis of immunodeficiency or is receiving chronic systemic steroid therapy (in dosing exceeding 10 mg daily of prednisone equivalent) or any other form of immunosuppressive therapy within 14 days prior to the first dose of study intervention.
• Uncontrolled diabetes mellitus, defined as Hgb-A1c ≥8% or Hgb-A1c between 7% and <8% with associated diabetes symptoms (polyuria or polydipsia) that are not otherwise explained.
• Known to be positive for hepatitis B by surface antigen expression. Known to have active hepatitis C infection (positive by polymerase chain reaction [PCR] or on antiviral therapy for hepatitis C within the last 6 months). Participants who have been treated for hepatitis C infection are permitted if they have documented sustained virologic response of 12 weeks.-. Known to be positive for HIV except for participants with controlled HIV infection on a stable regimen of ART. The investigator should ensure the ART does not result in substantial interactions with study or concomitant medications.
• Documented history of a cerebral vascular event (stroke or transient ischemic attack), unstable angina, myocardial infarction, congestive heart failure, or cardiac symptoms consistent with New York Heart Association Class III-IV within 6 months prior to their first dose of study intervention.
• History of noninfectious ILD or pneumonitis that required steroids, current ILD or pneumonitis, ≥Grade 3 pulmonary disease unrelated to underlying malignancy, prior radiation therapy to the lung that is >30 Gy within 6 months of the first dose of study treatment, and known diffusing capacity of the lung for carbon monoxide (DLCO), adjusted for hemoglobin <50% predicted. Participants with COPD are eligible if not requiring supplemental oxygen or systemic corticosteroids >10 mg daily prednisone or equivalent.
• Participants with inadequate organ function are excluded