AN OPEN-LABEL PHASE 1 STUDY TO EVALUATE PF-08046037 AS MONOTHERAPY AND PART OF COMBINATION THERAPY IN PARTICIPANTS WITH ADVANCED MALIGNANCIES

Overview

Sasanlimab (PF-06801591; RN-888; WHO 11161) is a humanized IgG4 monoclonal antibody targeting programmed death-1 (PD‑1). It is being developed as a subcutaneous (SC) checkpoint inhibitor dosed most commonly at 300 mg every 4 weeks. Preclinical work showed selective, high-affinity PD‑1 binding, blockade of PD‑L1/PD‑L2, and T‑cell activation without detectable Fc‑mediated effector function. Clinical development includes a pivotal phase 3 trial in BCG‑naïve, high‑risk non–muscle invasive bladder cancer (NMIBC) and early‑phase studies across solid tumors. (pubmed.ncbi.nlm.nih.gov)

Mechanism of action

• Binds PD‑1 on activated immune cells and blocks PD‑L1/PD‑L2 interactions, relieving inhibitory signaling and enhancing antitumor T‑cell responses; engineered as IgG4 with minimal Fc effector function. (pubmed.ncbi.nlm.nih.gov)
• Translational analyses from a first‑in‑human study found that higher baseline tumor mutational burden (TMB), PD‑L1, CD8, and interferon‑γ–related signatures were associated with better tumor shrinkage on sasanlimab across tumor types and IV/SC routes. (pubmed.ncbi.nlm.nih.gov)

Efficacy

Non–muscle invasive bladder cancer (BCG‑naïve, high‑risk; Phase 3 CREST, NCT04165317) - Randomized 1:1:1: sasanlimab+BCG induction+maintenance (Arm A; n=352) vs sasanlimab+BCG induction only (Arm B; n=352) vs BCG induction+maintenance (Arm C; n=351). Primary endpoint met: event‑free survival (EFS) improved for Arm A vs Arm C (HR 0.68; 95% CI 0.49–0.94; one‑sided p=0.0095). Estimated 36‑month EFS: 82.1% (Arm A) vs 74.8% (Arm C). Benefit was consistent in CIS and T1 subgroups. (pubmed.ncbi.nlm.nih.gov)
- Key secondary comparison (Arm B vs Arm C) was negative (HR 1.16; p=0.312), underscoring the role of BCG maintenance in the combination. In patients with CIS at randomization, complete response (CR) at any time was 89.8% with sasanlimab+BCG induction+maintenance vs 85.2% with BCG alone; 36‑month CR maintenance among responders was 91.7% vs 67.7%, respectively. Median OS not different at interim analysis (~41‑month follow‑up); study ongoing. (pfizer.com)

Advanced solid tumors (Phase Ib/II; SC 300 mg Q4W) - Dose‑expansion cohorts showed confirmed objective response rates (ORR): 16.4% in NSCLC (n=68) and 18.4% in urothelial carcinoma (n=38). Median PFS was 3.7 months (NSCLC) and 2.9 months (urothelial); median OS 14.7 and 10.9 months, respectively. Responses and survival tended to be higher with elevated PD‑L1 and high TMB. (pmc.ncbi.nlm.nih.gov)

Alternative SC dosing (Phase Ib/II) - A randomized pharmacokinetic study in advanced NSCLC/other malignancies evaluated 300 mg Q4W vs 600 mg Q6W SC dosing; it characterized exposure targets and supported SC schedules for further study. (pmc.ncbi.nlm.nih.gov)

Safety

• In phase Ib/II expansion (SC 300 mg Q4W), grade ≥3 treatment‑related adverse events (TRAEs) occurred in 13.2% of patients; overall tolerability was described as favorable. (pmc.ncbi.nlm.nih.gov)
• In the phase 3 CREST trial, the safety profile of sasanlimab+BCG was reported as consistent with known PD‑1 inhibitor class effects; no new safety signals were highlighted in topline disclosures. (reuters.com)

Further reading

• Preclinical characterization of sasanlimab (mechanism/engineering): Al‑Khami et al., Mol Cancer Ther 2020. (aacrjournals.org)
• Biomarker analyses across tumor types and routes (first‑in‑human): Salgado et al., 2021. (pubmed.ncbi.nlm.nih.gov)
• Phase Ib/II SC sasanlimab in NSCLC and urothelial carcinoma (efficacy/safety): Cho et al., ESMO Open 2023. (pmc.ncbi.nlm.nih.gov)
• Alternative SC dosing PK/safety: Penkov et al., Ther Adv Med Oncol 2024 (open access). (pmc.ncbi.nlm.nih.gov)
• Phase 3 CREST primary results in BCG‑naïve, high‑risk NMIBC: PubMed record and company summary. (pubmed.ncbi.nlm.nih.gov)
• Company development page (mechanism, administration, development status, updated Aug 5, 2025). (pfizeroncologydevelopment.com)

Last updated: Oct 2025

Overview

PF-08046037 (formerly SGN‑PDL1iT) is an investigational, PD‑L1–targeted immune‑stimulating antibody conjugate (ISAC) being developed by Pfizer (following the Seagen acquisition). A first‑in‑human, open‑label phase 1 study (NCT06974734) is recruiting in the United States and Puerto Rico to evaluate PF‑08046037 as monotherapy and in combination with the anti–PD‑1 antibody sasanlimab in advanced solid tumors (NSCLC, HNSCC, melanoma, PDAC). As of July–October 2025 updates, no human efficacy or safety results have been reported. (pfizeroncologydevelopment.com)

Mechanism of action

• Drug class: immune‑stimulating antibody conjugate (ISAC).
• Target: PD‑L1 on tumor and tumor‑associated antigen‑presenting cells (APCs).
• Payload: an imidazoquinoline‑based Toll‑like receptor 7 (TLR7) agonist, linked via a mannosidase‑cleavable linker; the antibody Fc is engineered to reduce FcγR binding, and the payload is designed with low membrane permeability to minimize off‑target immune activation.
• Proposed pharmacology: upon PD‑L1 binding and internalization into APCs, endosomal TLR7 activation triggers myeloid and dendritic cell activation, repolarizes the tumor microenvironment, enhances antigen presentation, and promotes adaptive anti‑tumor immunity. Preclinical in vitro and in vivo models demonstrated target‑dependent TLR7 activation and anti‑tumor activity. (aacrjournals.org)

Clinical development status

• Trial: NCT06974734, phase 1, open‑label dose escalation/optimization/expansion of PF‑08046037 as monotherapy and with sasanlimab; planned enrollment approximately 399 participants; dosing every 3 weeks (IV PF‑08046037; SC sasanlimab). Trial sites in the U.S. and Puerto Rico are recruiting. No clinical readouts have been posted as of the latest updates (July–October 2025). (pfizeroncologydevelopment.com)

Further reading

• AACR 2025 preclinical abstract describing PF‑08046037’s construct, linker, payload, and preclinical activity: “PF‑08046037, a PD‑L1 targeted TLR7 agonist ISAC, drives innate immune activation and anti‑tumor efficacy in preclinical in vitro and in vivo models.” (aacrjournals.org)
• Pfizer Oncology Development page for PF‑08046037 (mechanism summary and trial design for NCT06974734). (pfizeroncologydevelopment.com)
• Yale Medicine trial listing with key eligibility and dosing cadence for NCT06974734. (yalemedicine.org)
• ICH GCP mirror of the ClinicalTrials.gov record for NCT06974734 (status, planned enrollment, update dates). (ichgcp.net)

Note: PF‑08046037 (ISAC; “SGN‑PDL1iT”) is distinct from Seagen’s PD‑L1 vedotin ADC (SGN‑PDL1V; PF‑08046054), which has separate early clinical data and should not be conflated. (oncologypro.esmo.org)

Last updated: Oct 2025

This study is seeking participants who have the following tumor types and can provide tumor tissue samples as per below.

1. Tumor types

* Monotherapy Dose Escalation (Part 1a) and Optimization (Part 2a) cohorts

* Advanced or metastatic NSCLC, HNSCC, melanoma, or PDAC

* Must have progressive disease following at least 1 prior approved systemic therapy

* Monotherapy Dose Expansion (Part 3a)

• Advanced or metastatic NSCLC or PDAC

* Combination Safety Evaluation (Part 1b) and Dose Optimization (Part 2b)

* Advanced or metastatic NSCLC or HNSCC

* May be either a) not received prior immunotherapy for the tumor type OR b) relapse/ refractory after prior immunotherapy

* Combination Dose Expansion (Part 3b)

* Unresectable locally advanced or metastatic HNSCC or NSCLC

* Must not have received prior systemic cytotoxic therapy in the locally advanced or metastatic setting (first-line setting)

* Must be treatment naïve to any immunotherapy

* NSCLC must have PD-L1 expression TPS \>=50%

* HNSCC must have PD-L1 expression CPS \>=1

2. Tissue requirement

* Part 1 at lower doses: sufficient archival tissue collected within 12 months of enrollment for submission to central laboratory

* Part 1 at higher doses: de novo baseline tumor biopsy or archival tissue within 12 months of enrollment

* Part 1 backfill: de novo baseline and on-treatment tumor biopsies are required

* Part 2 and 3: de novo baseline or archival tissue within 6 months of enrollment

* Part 2 and 3: mandatory on-treatment tumor biopsy, if required by sponsor

3. Measurable disease per RECIST v1.1

Participants who meet the following might not be able to participate.

1. History of Grade \>=3 immune mediated AE related to prior immune modulatory therapy and required immunosuppressive therapy

2. Active or prior autoimmune disease that might deteriorate when receiving an immunostimulatory agent

3. History of uveitis within the preceding 6 months

4. Clinically significant Grade \>=3 neurodegenerative disease

5. Grade 3 or higher pulmonary disease unrelated to underlying malignancy

6. Previous exposure to an investigational immunostimulatory antibody conjugate or systemic TLR agonist