Study of Zanzalintinib (XL092) + Pembrolizumab vs Pembrolizumab in Subjects With PD-L1 Positive Recurrent or Metastatic Head and Neck Squamous Cell Carcinoma (STELLAR-305)

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

This is a multicenter, randomized, double-blind, controlled Phase 2/3 trial of zanzalintinib in combination with pembrolizumab versus zanzalintinib-matched placebo in combination with pembrolizumab in subjects with programmed death-ligand 1 (PD-L1) positive recurrent or metastatic head and neck squamous cell carcinoma (R/M HNSCC) incurable by local therapies who have not received prior systemic therapy for recurrent or metastatic disease.

Study Overview

• Status: Active, not recruiting
• Conditions: Head and Neck Squamous Cell Carcinoma
• Intervention / Treatment: Drug: Zanzalintinib; Biological: Pembrolizumab; Drug: Zanzalintinib-matched Placebo

• Study Type: Interventional
• Enrollment (Estimated): 600
• Phase: Phase 2; Phase 3

Contacts and Locations

Study Locations

• Argentina
  • Buenos Aires, Argentina, C1428AQK
    • Exelixis Clinical Site #91
  • Ciudad Autonoma de Buenos Aire, Argentina, C1015ABO
    • Exelixis Clinical Site # 47
  • Ciudad Autonoma de Buenos Aire, Argentina, C1056ABJ
    • Exelixis Clinical Site #53
  • Cordoba, Argentina, X5000JHQ
    • Exelixis Clinical Site #93
  • Córdoba, Argentina, X5008HHW
    • Exelixis Clinical Site #64
  • Pergamino, Argentina, B2700CPM
    • Exelixis Clinical Site #157
  • Santa Fe, Argentina, S3000FFU
    • Exelixis Clinical Site #92
  • Santa Fe
    • Rosario, Santa Fe, Argentina, S2000KZE
      • Exelixis Clinical Site #73
• Australia
  • Adelaide, Australia, 5000
    • Exelixis Clinical Site # 46
  • Bedford Park, Australia, 5042
    • Exelixis Clinical Site #154
  • Camperdown, Australia, NSW 2050
    • Exelixis Clinical Site #137
  • Murdoch, Australia, 6150
    • Exelixis Clinical Site #39
  • New South Wales
    • Port Macquarie, New South Wales, Australia, 2444
      • Exelixis Clinical Site #57
• Austria
  • Linz, Austria, 4010
    • Exelixis Clinical Site #156
  • Salzburg, Austria, 5020
    • Exelixis Clinical Site #42
  • Vienna, Austria, 1090
    • Exelixis Clinical Site #166
• Belgium
  • Bruxelles, Belgium, 1200
    • Exelixis Clinical Site #22
  • Charleroi, Belgium, 6000
    • Exelixis Clinical Site #106
  • Libramont, Belgium, 6800
    • Exelixis Clinical Site #14
  • Sint-Niklaas, Belgium, 9100
    • Exelixis Clinical Site #37
• Brazil
  • Barretos, Brazil, 14784 400
    • Exelixis Clinical Site #116
  • Curitiba, Brazil, 80810 050
    • Exelixis Clinical Site #75
  • Curitiba, Brazil, 81520 060
    • Exelixis Clinical Site #101
  • Porto Alegre, Brazil, 90110 270
    • Exelixis Clinical Site #97
  • Recife, Brazil, 50070 225
    • Exelixis Clinical Site #102
  • Rio de Janeiro, Brazil, 20230 130
    • Exelixis Clinical Site #87
  • Sao Paulo, Brazil, 1221020
    • Exelixis Clinical Site #88
  • São Paulo, Brazil, 01323 030
    • Exelixis Clinical Site #76
  • São Paulo, Brazil, 01525 001
    • Exelixis Clinical Site #77
  • São Paulo, Brazil, 04014-002
    • Exelixis Clinical Site #67
  • São Paulo, Brazil, 05403 900
    • Exelixis Clinical Site #98
  • Rio Grande Do Sul
    • Passo Fundo, Rio Grande Do Sul, Brazil, 99010-260
      • Exelixis Clinical Site #68
    • Porto Alegre, Rio Grande Do Sul, Brazil, 91350 200
      • Exelixis Clinical Site #90
  • Sao Paulo
    • Jau, Sao Paulo, Brazil, 17210 190
      • Exelixis Clinical Site #110
    • Santo André, Sao Paulo, Brazil, 09060-650
      • Exelixis Clinical Site #65
    • São José Do Rio Preto, Sao Paulo, Brazil, 15090 000
      • Exelixis Clinical Site #83
• Bulgaria
  • Plovdiv, Bulgaria, 4004
    • Exelixis Clinical Site #25
  • Ruse, Bulgaria, 7002
    • Exelixis Clinical Site #94
  • Sofia, Bulgaria, 1330
    • Exelixis Clinical Site #15
  • Sofia, Bulgaria, 1527
    • Exelixis Clinical Site #11
  • Sofia, Bulgaria, 1797
    • Exelixis Clinical Site #54
• Chile
  • Santiago, Chile, 13127
    • Exelixis Clinical Site #33
  • Santiago, Chile, 7500859
    • Exelixis Clinical Site #52
  • Santiago, Chile, 8331143
    • Exelixis Clinical Site #38
  • Santiago, Chile, 8940577
    • Exelixis Clinical Site #109
  • Talca, Chile, 3465586
    • Exelixis Clinical Site #50
  • Valdivia, Chile, 5090000
    • Exelixis Clinical Site #51
  • Viña Del Mar, Chile, 2540364
    • Exelixis Clinical Site #40
• Colombia
  • Barranquilla, Colombia, 80020
    • Exelixis Clinical Site #96
  • Bogota, Colombia, 129
    • Exelixis Clinical Site #152
  • Floridablanca, Colombia, 6810002
    • Exelixis Clinical Site #103
  • Pasto, Colombia, 520001
    • Exelixis Clinical Site #146
  • Pereira, Colombia, 660001
    • Exelixis Clinical Site #149
• Czechia
  • Nový Jičín, Czechia, 74101
    • Exelixis Clinical Site #49
  • Olomouc, Czechia, 77900
    • Exelixis Clinical Site #58
  • Prague, Czechia, 14059
    • Exelixis Clinical Site #34
  • Praha, Czechia, 10 10034
    • Exelixis Clinical Site #151
  • Praha, Czechia, 15006
    • Exelixis Clinical Site #48
  • Praha, Czechia, 18081
    • Exelixis Clinical Site #36
• France
  • Dijon Cedex, France, 21000
    • Exelixis Clinical Site #144
  • Grenoble Cedex, France, 09 38043
    • Exelixis Clinical Site #141
  • Lille cedex, France, 59000
    • Exelixis Clinical Site #140
  • Paris, France, 75013
    • Exelixis Clinical Site #26
  • Pierre Benite Cedex, France, 69004
    • Exelixis Clinical Site #112
  • Poitiers, France, 86021
    • Exelixis Clinical Site #105
  • Bouches-du-Rhône
    • Marseille, Bouches-du-Rhône, France, 13005
      • Exelixis Clinical Site #28
  • Gironde
    • Bordeaux, Gironde, France, 33075
      • Exelixis Clinical Site #16
  • Ille Et Vilaine
    • Rennes, Ille Et Vilaine, France, 35042
      • Exelixis Clinical Site #44
  • Loire
    • Saint Priest en Jarez, Loire, France, 42270
      • Exelixis Clinical Site #108
  • Rhone
    • Lyon, Rhone, France, 69008
      • Exelixis Clinical Site #70
  • Sarthe
    • Le Mans, Sarthe, France, 72000
      • Exelixis Clinical Site #107
  • Val De Marne
    • Villejuif, Val De Marne, France, 94805
      • Exelixis Clinical Site #66
• Germany
  • Giessen, Germany, 35392
    • Exelixis Clinical Site #167
• Greece
  • Athens, Greece, 11527
    • Exelixis Clinical Site #155
  • Athens, Greece, 12462
    • Exelixis Clinical Site #129
  • Larissa, Greece, 41500
    • Exelixis Clinical Site #159
  • Thessaloniki, Greece, 54622
    • Exelixis Clinical Site #120
  • Thessaloniki, Greece, 56403
    • Exelixis Clinical Site #150
  • Thessaloniki, Greece, 57001
    • Exelixis Clinical Site #128
• Hungary
  • Budapest, Hungary, 1083
    • Exelixis Clinical Site #125
  • Kecskemet, Hungary, 6000
    • Exelixis Clinical Site #99
  • Salgotarjan, Hungary, 3100
    • Exelixis Clinical Site #131
  • Szekszard, Hungary, 7100
    • Exelixis Clinical Site #147
• Israel
  • Haifa, Israel, 3109601
    • Exelixis Clinical Site #132
  • Haifa, Israel, 3436212
    • Exelixis Clinical Site #85
  • Jerusalem, Israel, 911201
    • Exelixis Clinical Site #74
  • Ramat Gan, Israel, 5265601
    • Exelixis Clinical Site #122
  • Tel Aviv, Israel, 6423906
    • Exelixis Clinical Site #86
• Italy
  • Brescia, Italy, 25124
    • Exelixis Clinical Site #35
  • Catania, Italy, 95123
    • Exelixis Clinical Site #45
  • Milano, Italy, 20133
    • Exelixis Clinical Site #81
  • Milano, Italy, 20141
    • Exelixis Clinical Site #55
  • Napoli, Italy, 80131
    • Exelixis Clinical Site #18
  • Rome, Italy, 0168
    • Exelixis Clinical Site #78
  • Rozzano, Italy, 20089
    • Exelixis Clinical Site #124
  • Verona, Italy, 37134
    • Exelixis Clinical Site #10
  • Torino
    • Candiolo, Torino, Italy, 10060
      • Exelixis Clinical Site #21
• Korea, Republic of
  • Busan, Korea, Republic of, 49201
    • Exelixis Clinical Site #13
  • Seoul, Korea, Republic of, 3722
    • Exelixis Clinical Site #5
  • Seoul, Korea, Republic of, 5505
    • Exelixis Clinical Site #63
  • Seoul, Korea, Republic of, 6273
    • Exelixis Clinical Site #12
  • Seoul, Korea, Republic of, 6591
    • Exelixis Clinical Site #6
  • Seoul, Korea, Republic of, 8308
    • Exelixis Clinical Site #29
  • Gangwon-do
    • Busan, Gangwon-do, Korea, Republic of, 49267
      • Exelixis Clinical Site #7
  • Gyeonggi-do
    • Suwon, Gyeonggi-do, Korea, Republic of, 16499
      • Exelixis Clinical Site #17
    • Suwon-si, Gyeonggi-do, Korea, Republic of, 16247
      • Exelixis Clinical Site #30
  • Gyeongsangnam-do
    • Yangsan, Gyeongsangnam-do, Korea, Republic of, 50612
      • Exelixis Clinical Site #9
  • Jeollabuk Do
    • Jeonju, Jeollabuk Do, Korea, Republic of, 54907
      • Exelixis Clinical Site #69
  • Jeollabuk-do
    • Jeonju, Jeollabuk-do, Korea, Republic of, 54907
      • Exelixis Clinical Site #8
• Malaysia
  • Kuala Lumpur, Malaysia, 50586
    • Exelixis Clinical Site #60
  • Kuala Lumpur, Malaysia, 59100
    • Exelixis Clinical Site #72
  • Kuala Lumpur
    • Putrajaya, Kuala Lumpur, Malaysia, 62250
      • Exelixis Clinical Site #61
• Mexico
  • Guadalajara, Mexico, 44280
    • Exelixis Clinical Site #168
  • Jalisco
    • Guadalajara, Jalisco, Mexico, 44160
      • Exelixis Clinical Site #114
  • Queretaro
    • San Juan del Rio, Queretaro, Mexico, 76800
      • Exelixis Clinical Site #119
• Poland
  • Gliwice, Poland, 44 102
    • Exelixis Clinical Site #139
  • Torun, Poland, 87 100
    • Exelixis Clinical Site #162
  • Trybunalski
    • Piotrkow, Trybunalski, Poland, 97 300
      • Exelixis Clinical Site #89
• Romania
  • Bucuresti, Romania, 030463
    • Exelixis Clinical Site #160
  • Cluj-Napoca, Romania, 400641
    • Exelixis Clinical Site #24
  • Craiova, Romania, 200542
    • Exelixis Clinical Site #20
  • Floreşti, Romania, 407280
    • Exelixis Clinical Site #104
  • Ploiesti, Romania, 100337
    • Exelixis Clinical Site #127
  • Timisoara, Romania, 300239
    • Exelixis Clinical Site #143
• Slovakia
  • Košice, Slovakia, 04191
    • Exelixis Clinical Site #23
  • Trnava, Slovakia, 91775
    • Exelixis Clinical Site #27
  • Zilina, Slovakia, 01207
    • Exelixis Clinical Site #121
• Spain
  • Barcelona, Spain, 08025
    • Exelixis Clinical Site #115
  • Girona, Spain, 17007
    • Exelixis Clinical Site #113
  • La Coruna, Spain, 15009
    • Exelixis Clinical Site #130
  • Madrid, Spain, 28027
    • Exelixis Clinical Site #134
  • Madrid, Spain, 28033
    • Exelixis Clinical Site #111
  • Madrid, Spain, 28034
    • Exelixis Clinical Site #32
  • Madrid, Spain, 28040
    • Exelixis Clinical Site #59
  • Madrid, Spain, 28046
    • Exelixis Clinical Site #31
  • Pamplona, Spain, 31008
    • Exelixis Clinical Site #136
  • Sevilla, Spain, 41009
    • Exelixis Clinical Site #126
  • Valencia, Spain, 46009
    • Exelixis Clinical Site #153
  • Zaragoza, Spain, 50009
    • Exelixis Clinical Site #41
• Taiwan
  • Kaohsiung, Taiwan, 807
    • Exelixis Clinical Site #145
  • Taichung, Taiwan, 40447
    • Exelixis Clinical Site #164
  • Taipei, Taiwan, 100229
    • Exelixis Clinical Site #118
  • Taipei City, Taiwan, 11217
    • Exelixis Clinical Site #142
  • Taoyuan, Taiwan, 33305
    • Exelixis Clinical Site #165
• Thailand
  • Bangkok, Thailand, 10330
    • Exelixis Clinical Site #80
  • Bangkok
    • Bangkoknoi, Bangkok, Thailand, 10700
      • Exelixis Clinical Site #71
  • Chiang Mai
    • Chiangmai, Chiang Mai, Thailand, 50200
      • Exelixis Clinical Site #56
  • Songkhla
    • Hat Yai, Songkhla, Thailand, 90110
      • Exelixis Clinical Site #79
• United Kingdom
  • Manchester, United Kingdom, M20 4BX
    • Exelixis Clinical Site #138
  • Sutton, United Kingdom, SM2 5PT
    • Exelixis Clinical Site #133
  • Torquay, United Kingdom, TQ2 7AA
    • Exelixis Clinical Site #161
  • England
    • London, England, United Kingdom, SW36JJ
      • Exelixis Clinical Site #135
  • Essex
    • Romford, Essex, United Kingdom, RM7 0AG
      • Exelixis Clinical Site #84
• United States
  • California
    • Fullerton, California, United States, 92835
      • Exelixis Clinical Site #2
  • Florida
    • Orange City, Florida, United States, 32763
      • Exelixis Clinical Site #1
    • Tampa, Florida, United States, 33612-9497
      • Exelixis Clinical Site #163
  • Georgia
    • Athens, Georgia, United States, 30607
      • Exelixis Clinical Site #123
    • Atlanta, Georgia, United States, 30322
      • Exelixis Clinical Site #82
  • Illinois
    • Chicago, Illinois, United States, 60611
      • Exelixis Clinical Site #19
  • Iowa
    • Des Moines, Iowa, United States, 50309
      • Exelixis Clinical Site #62
    • Iowa City, Iowa, United States, 52242
      • Exelixis Clinical Site #100
  • Missouri
    • Saint Louis, Missouri, United States, 63110
      • Exelixis Clinical Site #4
  • New Hampshire
    • Lebanon, New Hampshire, United States, 03756
      • Exelixis Clinical Site #148
  • New Jersey
    • Camden, New Jersey, United States, 08103
      • Exelixis Clinical Site #158
  • New York
    • Shirley, New York, United States, 11967
      • Exelixis Clinical Site #3
  • North Carolina
    • Durham, North Carolina, United States, 27710
      • Exelixis Clinical Site #95
    • Wilson, North Carolina, United States, 27893
      • Exelixis Clinical Site #117
  • Virginia
    • Roanoke, Virginia, United States, 24014
      • Exelixis Clinical Site #43

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

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

  • 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.
• Participants with oropharyngeal cancer must have human papillomavirus (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 (for example, cytotoxic T-lymphocyte-associated protein 4 (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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Zanzalintinib + Pembrolizumab; Subjects with R/M HNSCC will receive zanzalintinib + pembrolizumab	Drug: Zanzalintinib; Specified doses on specified days; Other Names: XL092; Biological: Pembrolizumab; Specified doses on specified days; Other Names: KEYTRUDA®
Placebo Comparator: Zanzalintinib-Matched Placebo + Pembrolizumab; Subjects with R/M HNSCC will receive zanzalintinib-matched placebo + pembrolizumab	Biological: Pembrolizumab; Specified doses on specified days; Other Names: KEYTRUDA®; Drug: Zanzalintinib-matched Placebo; Specified doses on specified days; Other Names: XL092-matched Placebo

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Progression-Free Survival (PFS) per Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST 1.1) by Blinded Independent Central Review (BICR)	Defined as the time from randomization to the earlier of either radiographic progressive disease (PD) per RECIST 1.1 as determined by the BICR or death from any cause	Approximately 33 months after the first subject is randomized
Overall Survival (OS)	Defined as the time from randomization to death due to any cause	Approximately 50 months after the first subject is randomized

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
PFS per RECIST 1.1 by Investigator	Defined as the time from randomization to the earlier of either radiographic PD per RECIST 1.1 as determined by the Investigator or death from any cause	Approximately 33 months after the first subject is randomized
Objective Response Rate (ORR) per RECIST 1.1 by the BICR and Investigator	Defined as the proportion of subjects with the best overall response of complete response (CR) or partial response (PR) per RECIST 1.1 as determined by the BICR and Investigator	Approximately 33 months after the first subject is randomized
Duration of Response (DOR) Per RECIST 1.1 by BICR and Investigator	Defined as the time from the first documentation of objective response (subsequently confirmed at a visit ≥ 28 days later) to disease progression or death due to any cause	Approximately 33 months after the first subject is randomized

Collaborators and Investigators

• Sponsor: Exelixis
• Collaborators: Merck Sharp & Dohme LLC

Study record dates

Study Major Dates

• Study Start (Actual): June 7, 2024
• Primary Completion (Estimated): August 1, 2028
• Study Completion (Estimated): March 1, 2029

Study Registration Dates

• First Submitted: October 9, 2023
• First Submitted That Met QC Criteria: October 9, 2023
• First Posted (Actual): October 13, 2023

Study Record Updates

• Last Update Posted (Actual): August 17, 2025
• Last Update Submitted That Met QC Criteria: August 13, 2025
• Last Verified: August 1, 2025

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Neoplasms by Site; Neoplasms; Neoplasms by Histologic Type; Head and Neck Neoplasms; Neoplasms, Glandular and Epithelial; Neoplasms, Squamous Cell; Squamous Cell Carcinoma of Head and Neck; Carcinoma; Carcinoma, Squamous Cell; Antineoplastic Agents, Immunological; Immune Checkpoint Inhibitors; Antineoplastic Agents; Molecular Mechanisms of Pharmacological Action; Pembrolizumab
• Other Study ID Numbers: XL092-305; KEYNOTE-G06; EU CTR: 2023-506308-24-00 (Other Identifier: European Medicines Agency); KEYNOTE-G06 (Other Identifier: Merck Sharp & Dohme LLC); MK-3475-G06 (Other Identifier: Merck Sharp & Dohme LLC)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No