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PF-08634404 plus chemotherapy versus pembrolizumab-based chemotherapy for advanced non-small cell lung cancer

AN INTERVENTIONAL PHASE 3, DOUBLE-BLIND, RANDOMIZED STUDY TO EVALUATE EFFICACY AND SAFETY OF PF-08634404 IN COMBINATION WITH CHEMOTHERAPY VERSUS PEMBROLIZUMAB IN COMBINATION WITH CHEMOTHERAPY IN ADULT PARTICIPANTS WITH LOCALLY ADVANCED OR METASTATIC NON-SMALL CELL LUNG CANCER

Phase 3 Interventional Pfizer · NCT07222566

This will test whether PF-08634404 combined with chemotherapy works better than pembrolizumab plus chemotherapy for adults with locally advanced or metastatic non-small cell lung cancer who have not received prior treatment for their advanced disease.

Quick facts

PhasePhase 3
Study typeInterventional
Enrollment1410 (estimated)
Ages18 Years and up
SexAll
SponsorPfizer Industry-sponsored
Drugs / interventionsimmunotherapy, pembrolizumab, chemotherapy
Locations229 sites (Bullhead City, Arizona and 228 other locations)
Trial IDNCT07222566 on ClinicalTrials.gov

What this trial studies

This Phase 3 trial randomizes adults with locally advanced or metastatic squamous or non-squamous NSCLC, who are treatment-naïve for advanced disease and lack actionable genomic alterations, to receive either PF-08634404 with chemotherapy or the current standard pembrolizumab with chemotherapy. Participants are assigned to one of two parts based on tumor histology (squamous versus non-squamous) and must have measurable disease and ECOG 0–1. The study will compare clinical outcomes and safety between the two regimens, using standard oncology endpoints such as progression and survival while monitoring adverse events. Tissue and PD-L1 status are required at baseline to support stratification and analysis.

Who should consider this trial

Good fit: Adults (≥18) with pathologically confirmed locally advanced (IIIB/IIIC) or metastatic (IV) squamous or non-squamous NSCLC who are treatment-naïve for advanced disease, lack known actionable genomic alterations, have ECOG performance status 0–1, and have measurable disease.

Not a fit: Patients with known actionable genomic alterations (for example EGFR or ALK), prior systemic therapy for advanced disease, poor performance status, or those who are candidates for curative surgery or chemoradiotherapy are unlikely to benefit from this study.

Why it matters

Potential benefit: If successful, this regimen could offer a more effective first-line option that prolongs survival or delays progression compared with current pembrolizumab-based chemotherapy.

How similar studies have performed: Pembrolizumab plus chemotherapy is an established first-line standard of care, while prior efforts to add novel targeted or immunomodulatory agents to chemotherapy have shown mixed results; the PF-08634404 combination is a novel approach that has not yet been proven.

Eligibility criteria

Show full inclusion / exclusion criteria 
Inclusion Criteria:

* 18 years of age or older at screening.
* Have pathologically confirmed locally advanced (Stage IIIB/IIIC) or metastatic (Stage IV)squamous or non-squamous NSCLC and not be a candidate for complete surgical resection and curative concurrent/sequential chemoradiotherapy (according to the 9th edition of the Union for International Cancer Control and American Joint Committee on Cancer lung cancer Tumor, lymph nodes, metastasis (TNM) staging system).
* Have tumor tissue available, either paraffin block or slides from a core, excisional or fine needle biopsy
* PD-L1 status available based on local testing results
* Measurable disease based on RECIST v1.1 per investigator.
* Eastern Cooperative Oncology Group performance status (ECOG) score of 0 or 1
* Expected survival ≥12 weeks

Exclusion Criteria:

* Participants with known actionable genomic alteration (AGAs), including estimated glomerular filtration rate (EGFR), anaplastic lymphoma kinase (ALK), Repressor of Silencing 1 (ROS1), neurotrophic tyrosine receptor kinase (NTRK), v-raf murine sarcoma viral oncogene homolog B1 (BRAF), rearranged during transfection (RET), and mesenchymal-epithelial transition (MET), for which there are available first-line therapies per local standard-of-care (SOC) are ineligible. Documented negative results for EGFR, ALK, and ROS1 AGAs are required for participants with non-squamous histology.
* Known active CNS lesions are excluded. Participants with definitively treated brain metastases (surgery and/or radiotherapy) may be eligible. Clinically inactive brain metastases of longest diameter \< 1 cm are permitted.
* Participants with clinically significant risk of hemorrhage or fistula are excluded.
* Participants with any 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.
* Unresolved toxicities from prior anti-tumor therapy, that did not recover to NCI CTCAE v5.0 Grade 0 or 1.
* Known to have a history of a severe allergy to any component of the study intervention, or a history of severe allergic reaction to chimeric or humanized antibody.
* History of allogeneic organ / hematopoietic stem cell transplantation.
* Participants with any of the following respiratory conditions:
* Evidence of noninfectious or drug-induced interstitial lung disease (ILD) or pneumonitis
* Grade ≥3 pulmonary disease unrelated to underlying malignancy
* History of uncontrolled comorbidities within 6 months prior to the first dose including uncontrolled cardiac and cerebrovascular conditions, hypertension, diabetes, significant vascular disease or arterial/severe venous thromboembolic events.
* Major surgery \< 4 weeks or minor surgery \< 3 days prior to first dose of study intervention.
* History of severe bleeding tendency or coagulation dysfunction
* History of esophageal varices, severe ulcers, unhealed wounds, gastrointestinal perforation, abdominal fistula, gastrointestinal obstruction, intra-abdominal abscess, or acute gastrointestinal bleeding within 6 months prior to the first dose.
* Participants with acute, chronic or symptomatic infections including participants positive for active HIV, hepatitis B virus (HBV), or Hepatitis C virus (HCV).
* Participants with history of immunodeficiency
* Any medical or psychiatric condition including recent (within the past year) or active suicidal ideation/behavior (in the past 5 years) or laboratory abnormality that may increase the risk of study participation or make the participant inappropriate for the study.
* Previous systemic anti-tumor therapy including:

  1. Prior systemic therapy, including anti-PD-(L)1 therapy, for locally advanced, unresectable, or metastatic NSCLC.
  2. Previous treatment with immunotherapy
  3. Prior radiotherapy \> 30 Gy to the lung \< 6 months of first dose of study intervention
  4. Palliative local therapy \< 2 weeks before the first dose of study intervention;
  5. Non-specific immunomodulatory therapy \< 2 weeks before the first dose.
  6. Prior systemic anti-angiogenic therapy
* Prior immune-related AE that led to anti-PD-(L)1 treatment discontinuation, adverse events from prior immunotherapy not improved to Grade 1 before screening, or required treatment with systemic immunosuppressive therapy.
* Prior and concomitant therapy:

  1. therapeutic oral or parenteral anticoagulants or thrombolytic agents \< 10 days to the first dose.
  2. chronic antiplatelet therapy \<7 days to randomization.
  3. live or attenuated live vaccine \< 4 weeks to the first dose.
  4. current high-dose systemic corticosteroids.
  5. prohibited concomitant medication(s) \< 21 days to the first dose.
* Breastfeeding participants, participants of childbearing potential, and male participants who are unwilling to follow contraceptive measures.

Where this trial is running

Bullhead City, Arizona and 228 other locations

+179 more sites — see ClinicalTrials.gov for the full list.

Study contacts

How to participate

  1. Review the eligibility criteria above with your treating physician.
  2. Visit the official trial page on ClinicalTrials.gov for the most current contact information and recruitment status.
  3. Contact the listed study coordinator or principal investigator to request pre-screening. Pre-screening is free and never obligates you to enroll.
View on ClinicalTrials.gov → Find more trials like this →
Conditions Advanced Non-Small Cell Lung CancerNon-Small Cell Lung CancerCarcinoma, Non-Small-Cell LungMetastatic Non Small Cell Lung CancerLung Cancernon-squamous NSCLCsquamous NSCLCmetastatic squamous or non-squamous NSCLC
Last reviewed 2026-06-13 by the Find a Trial editorial team. Information on this page is for educational purposes and is not medical advice. Always consult qualified healthcare professionals about clinical trial participation.