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Combining Zanzalintinib with Pembrolizumab for Head and Neck Cancer

A Phase 2/3, Randomized, Double-Blind, Controlled Study of Zanzalintinib (XL092) in Combination With Pembrolizumab vs Pembrolizumab in First-Line Treatment of Subjects With PD-L1 Positive Recurrent or Metastatic Head and Neck Squamous Cell Carcinoma

Phase2; Phase3 Interventional Exelixis · NCT06082167

This study is testing if combining two drugs, zanzalintinib and pembrolizumab, can help people with advanced head and neck cancer that can't be treated with local therapies feel better compared to just using pembrolizumab alone.

Quick facts

PhasePhase2; Phase3
Study typeInterventional
Enrollment600 (estimated)
Ages18 Years and up
SexAll
SponsorExelixis Industry-sponsored
Drugs / interventionszanzalintinib, Radiation, pembrolizumab
Locations168 sites (Fullerton, California and 167 other locations)
Trial IDNCT06082167 on ClinicalTrials.gov

What this trial studies

This clinical trial evaluates the effectiveness of zanzalintinib in combination with pembrolizumab compared to a placebo with pembrolizumab in patients with PD-L1 positive recurrent or metastatic head and neck squamous cell carcinoma (HNSCC) that cannot be treated with local therapies. It is a multicenter, randomized, double-blind study designed to assess the safety and efficacy of this combination in patients who have not received prior systemic therapy for their condition. The trial aims to determine if this combination can improve outcomes for patients with this challenging cancer type.

Who should consider this trial

Good fit: Ideal candidates include individuals with PD-L1 positive recurrent or metastatic head and neck squamous cell carcinoma who have not undergone prior systemic therapy.

Not a fit: Patients with head and neck cancer that can be treated with local therapies or those who have received prior systemic therapy for recurrent or metastatic disease may not benefit from this study.

Why it matters

Potential benefit: If successful, this treatment could provide a new therapeutic option for patients with advanced head and neck cancer that is currently difficult to treat.

How similar studies have performed: Other studies have shown promising results with similar immunotherapy combinations, indicating potential for success in this approach.

Eligibility criteria

Show full inclusion / exclusion criteria 
Inclusion Criteria:

* Histologically or cytologically-confirmed R/M HNSCC that is considered incurable by local therapy.

  * Subjects should not have had prior systemic therapy administered in the recurrent or metastatic setting. Systemic therapy which was completed more than 6 months prior to randomization if given as part of multimodal treatment for locally advanced disease is allowed.
  * The eligible primary tumor locations are the oropharynx, oral cavity, hypopharynx, and larynx.
* PD-L1 expression level Combined Positive Score (CPS) ≥ 1.
* Subjects with oropharyngeal cancer must have HPV status from tumor tissue.
* Measurable disease according to RECIST 1.1 as determined by the Investigator.
* Tumor samples (archival or fresh tumor biopsy) are required. If archival tissue is unavailable, must provide fresh tumor tissue biopsy prior to randomization.
* Recovery to baseline or ≤ Grade 1 severity (CTCAE v5) from adverse events (AEs) related to any prior treatments, unless AE(s) are clinically nonsignificant and/or stable on supportive therapy.
* Age 18 years (or the legal age of consent in your country, if higher than 18) or older on the day of consent.
* Eastern Cooperative Oncology Group (ECOG) performance status of 0-1.
* Adequate organ and marrow function.

Exclusion Criteria:

* Nasopharynx, salivary gland or occult primary site (regardless of p16 status).
* Has disease that is suitable for local therapy administered with curative intent.
* Has received prior therapy with zanzalintinib, any anti-PD-1, anti-PD-L1, or anti-PD-L2 agent or with an agent directed to another stimulatory or co-inhibitory T-cell receptor (eg, CTLA-4, OX-40, CD137).
* Life expectancy \< 3 months.
* Had progressive disease within 6 months of completion of curatively intended systemic treatment for locoregionally advanced HNSCC.
* Radiation therapy for bone metastases within 2 weeks, any other radiation therapy within 4 weeks prior to randomization.
* Known brain metastases or cranial epidural disease unless adequately treated with radiotherapy and/or surgery (including radiosurgery) and stable for at least 4 weeks prior to randomization.
* Positive hepatitis B surface antigen (HBsAg) test.
* Positive hepatitis C virus (HCV) antibody test.
* Major surgery (eg, GI surgery, removal or biopsy of brain metastasis) within 8 weeks prior to randomization. Complete wound healing from major or minor surgery must have occurred at least prior to randomization.
* Corrected QT interval calculated by the Fridericia formula (QTcF) \> 480 ms per electrocardiogram (ECG) within 28 days before randomization.
* Pregnant or lactating females.
* Administration of a live, attenuated vaccine within 30 days before randomization.

Where this trial is running

Fullerton, California and 167 other locations

+118 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 Head and Neck Squamous Cell Carcinoma
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.