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

NCT06082167 | Active Not Recruiting Phase 2 DMC FDA Drug

• 4 other identifiers: XL092-305; KEYNOTE-G06EU CTR: 2023-506308-24-00KEYNOTE-G06MK-3475-G06
• Study Type: interventional
• Target: 600
• Locations: 25 countries
• Sites: 165

Brief Summary

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.

Conditions

Head and Neck Squamous Cell Carcinoma

Outcome Measures

Primary Outcomes (2)

• 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 Outcomes (3)

• PFS per RECIST 1.1 by Investigator

  Approximately 33 months after the first subject is randomized

• Objective Response Rate (ORR) per RECIST 1.1 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

  Approximately 33 months after the first subject is randomized

Study Arms (2)

Zanzalintinib + Pembrolizumab

EXPERIMENTAL

Subjects with R/M HNSCC will receive zanzalintinib + pembrolizumab

Drug: Zanzalintinib; Biological: Pembrolizumab

Zanzalintinib-Matched Placebo + Pembrolizumab

PLACEBO COMPARATOR

Subjects with R/M HNSCC will receive zanzalintinib-matched placebo + pembrolizumab

Drug: Zanzalintinib-matched Placebo; Biological: Pembrolizumab

Interventions

Zanzalintinib DRUG

Specified doses on specified days

Also known as: XL092

Zanzalintinib + Pembrolizumab

Zanzalintinib-matched Placebo DRUG

Specified doses on specified days

Also known as: XL092-matched Placebo

Zanzalintinib-Matched Placebo + Pembrolizumab

Pembrolizumab BIOLOGICAL

Specified doses on specified days

Also known as: KEYTRUDA®

Zanzalintinib + Pembrolizumab; Zanzalintinib-Matched Placebo + Pembrolizumab

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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.

You may not qualify if:

• 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.

Sponsors & Collaborators

• Exelixis: lead
• Merck Sharp & Dohme LLC: collaborator

Study Sites (168)

Exelixis Clinical Site #2

Fullerton, California, 92835, United States

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Exelixis Clinical Site #1

Orange City, Florida, 32763, United States

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Exelixis Clinical Site #163

Tampa, Florida, 33612-9497, United States

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Exelixis Clinical Site #123

Athens, Georgia, 30607, United States

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Exelixis Clinical Site #82

Atlanta, Georgia, 30322, United States

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Exelixis Clinical Site #19

Chicago, Illinois, 60611, United States

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Exelixis Clinical Site #62

Des Moines, Iowa, 50309, United States

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Exelixis Clinical Site #100

Iowa City, Iowa, 52242, United States

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Exelixis Clinical Site #4

St Louis, Missouri, 63110, United States

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Exelixis Clinical Site #148

Lebanon, New Hampshire, 03756, United States

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Exelixis Clinical Site #158

Camden, New Jersey, 08103, United States

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Exelixis Clinical Site #3

Shirley, New York, 11967, United States

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Exelixis Clinical Site #95

Durham, North Carolina, 27710, United States

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Exelixis Clinical Site #117

Wilson, North Carolina, 27893, United States

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Exelixis Clinical Site #43

Roanoke, Virginia, 24014, United States

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Exelixis Clinical Site #73

Rosario, Santa Fe Province, S2000KZE, Argentina

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Exelixis Clinical Site #91

Buenos Aires, C1428AQK, Argentina

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Exelixis Clinical Site # 47

Ciudad Autonoma de Buenos Aire, C1015ABO, Argentina

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Exelixis Clinical Site #53

Ciudad Autonoma de Buenos Aire, C1056ABJ, Argentina

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Exelixis Clinical Site #93

Córdoba, X5000JHQ, Argentina

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Exelixis Clinical Site #64

Córdoba, X5008HHW, Argentina

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Exelixis Clinical Site #157

Pergamino, B2700CPM, Argentina

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Exelixis Clinical Site #92

Santa Fe, S3000FFU, Argentina

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Exelixis Clinical Site #57

Port Macquarie, New South Wales, 2444, Australia

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Exelixis Clinical Site # 46

Adelaide, 5000, Australia

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Exelixis Clinical Site #154

Bedford Park, 5042, Australia

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Exelixis Clinical Site #137

Camperdown, NSW 2050, Australia

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Exelixis Clinical Site #39

Murdoch, 6150, Australia

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Exelixis Clinical Site #156

Linz, 4010, Austria

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Exelixis Clinical Site #42

Salzburg, 5020, Austria

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Exelixis Clinical Site #166

Vienna, 1090, Austria

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Exelixis Clinical Site #22

Brussels, 1200, Belgium

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Exelixis Clinical Site #106

Charleroi, 6000, Belgium

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Exelixis Clinical Site #14

Libramont, 6800, Belgium

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Exelixis Clinical Site #37

Sint-Niklaas, 9100, Belgium

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Exelixis Clinical Site #68

Passo Fundo, Rio Grande do Sul, 99010-260, Brazil

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Exelixis Clinical Site #90

Porto Alegre, Rio Grande do Sul, 91350 200, Brazil

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Exelixis Clinical Site #110

Jaú, São Paulo, 17210 190, Brazil

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Exelixis Clinical Site #65

Santo André, São Paulo, 09060-650, Brazil

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Exelixis Clinical Site #83

São José do Rio Preto, São Paulo, 15090 000, Brazil

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Exelixis Clinical Site #116

Barretos, 14784 400, Brazil

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Exelixis Clinical Site #75

Curitiba, 80810 050, Brazil

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Exelixis Clinical Site #101

Curitiba, 81520 060, Brazil

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Exelixis Clinical Site #97

Porto Alegre, 90110 270, Brazil

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Exelixis Clinical Site #102

Recife, 50070 225, Brazil

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Exelixis Clinical Site #87

Rio de Janeiro, 20230 130, Brazil

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Exelixis Clinical Site #76

São Paulo, 01323 030, Brazil

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Exelixis Clinical Site #77

São Paulo, 01525 001, Brazil

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Exelixis Clinical Site #67

São Paulo, 04014-002, Brazil

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Exelixis Clinical Site #98

São Paulo, 05403 900, Brazil

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Exelixis Clinical Site #88

São Paulo, 1221020, Brazil

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Exelixis Clinical Site #25

Plovdiv, 4004, Bulgaria

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Exelixis Clinical Site #94

Rousse, 7002, Bulgaria

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Exelixis Clinical Site #15

Sofia, 1330, Bulgaria

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Exelixis Clinical Site #11

Sofia, 1527, Bulgaria

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Exelixis Clinical Site #54

Sofia, 1797, Bulgaria

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Exelixis Clinical Site #33

Santiago, 13127, Chile

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Exelixis Clinical Site #52

Santiago, 7500859, Chile

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Exelixis Clinical Site #38

Santiago, 8331143, Chile

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Exelixis Clinical Site #109

Santiago, 8940577, Chile

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Exelixis Clinical Site #50

Talca, 3465586, Chile

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Exelixis Clinical Site #51

Valdivia, 5090000, Chile

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Exelixis Clinical Site #40

Viña del Mar, 2540364, Chile

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Exelixis Clinical Site #96

Barranquilla, 80020, Colombia

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Exelixis Clinical Site #152

Bogotá, 129, Colombia

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Exelixis Clinical Site #103

Floridablanca, 6810002, Colombia

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Exelixis Clinical Site #146

Pasto, 520001, Colombia

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Exelixis Clinical Site #149

Pereira, 660001, Colombia

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Exelixis Clinical Site #49

Nový Jičín, 74101, Czechia

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Exelixis Clinical Site #58

Olomouc, 77900, Czechia

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Exelixis Clinical Site #151

Prague, 10 10034, Czechia

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Exelixis Clinical Site #34

Prague, 14059, Czechia

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Exelixis Clinical Site #48

Prague, 15006, Czechia

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Exelixis Clinical Site #36

Prague, 18081, Czechia

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Exelixis Clinical Site #28

Marseille, Bouches-du-Rhône, 13005, France

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Exelixis Clinical Site #16

Bordeaux, Gironde, 33075, France

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Exelixis Clinical Site #44

Rennes, Ille Et Vilaine, 35042, France

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Exelixis Clinical Site #108

Saint Priest En Jarez, Pays de la Loire Region, 42270, France

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Exelixis Clinical Site #70

Lyon, Rhone, 69008, France

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Exelixis Clinical Site #107

Le Mans, Sarthe, 72000, France

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Exelixis Clinical Site #66

Villejuif, Val De Marne, 94805, France

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Exelixis Clinical Site #144

Dijon, 21000, France

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Exelixis Clinical Site #141

Grenoble, 09 38043, France

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Exelixis Clinical Site #140

Lille, 59000, France

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Exelixis Clinical Site #26

Paris, 75013, France

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Exelixis Clinical Site #112

Pierre-Bénite, 69004, France

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Exelixis Clinical Site #105

Poitiers, 86021, France

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Exelixis Clinical Site #167

Giessen, 35392, Germany

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Exelixis Clinical Site #155

Athens, 11527, Greece

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Exelixis Clinical Site #129

Athens, 12462, Greece

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Exelixis Clinical Site #159

Larissa, 41500, Greece

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Exelixis Clinical Site #120

Thessaloniki, 54622, Greece

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Exelixis Clinical Site #150

Thessaloniki, 56403, Greece

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Exelixis Clinical Site #128

Thessaloniki, 57001, Greece

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Exelixis Clinical Site #125

Budapest, 1083, Hungary

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Exelixis Clinical Site #99

Kecskemét, 6000, Hungary

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Exelixis Clinical Site #131

Salgótarján, 3100, Hungary

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Exelixis Clinical Site #147

Szekszárd, 7100, Hungary

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Exelixis Clinical Site #132

Haifa, 3109601, Israel

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Exelixis Clinical Site #85

Haifa, 3436212, Israel

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Exelixis Clinical Site #74

Jerusalem, 911201, Israel

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Exelixis Clinical Site #122

Ramat Gan, 5265601, Israel

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Exelixis Clinical Site #86

Tel Aviv, 6423906, Israel

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Exelixis Clinical Site #21

Candiolo, Torino, 10060, Italy

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Exelixis Clinical Site #35

Brescia, 25124, Italy

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Exelixis Clinical Site #45

Catania, 95123, Italy

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Exelixis Clinical Site #81

Milan, 20133, Italy

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Exelixis Clinical Site #55

Milan, 20141, Italy

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Exelixis Clinical Site #18

Napoli, 80131, Italy

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Exelixis Clinical Site #78

Rome, 0168, Italy

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Exelixis Clinical Site #124

Rozzano, 20089, Italy

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Exelixis Clinical Site #10

Verona, 37134, Italy

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Exelixis Clinical Site #61

Putrajaya, Kuala Lumpur, 62250, Malaysia

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Exelixis Clinical Site #60

Kuala Lumpur, 50586, Malaysia

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Exelixis Clinical Site #72

Kuala Lumpur, 59100, Malaysia

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Exelixis Clinical Site #114

Guadalajara, Jalisco, 44160, Mexico

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Exelixis Clinical Site #119

San Juan del Río, Querétaro, 76800, Mexico

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Exelixis Clinical Site #168

Guadalajara, 44280, Mexico

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Exelixis Clinical Site #89

Piotrków, Trybunalski, 97 300, Poland

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Exelixis Clinical Site #139

Gliwice, 44 102, Poland

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Exelixis Clinical Site #162

Torun, 87 100, Poland

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Exelixis Clinical Site #160

Bucharest, 030463, Romania

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Exelixis Clinical Site #24

Cluj-Napoca, 400641, Romania

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Exelixis Clinical Site #20

Craiova, 200542, Romania

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Exelixis Clinical Site #104

Floreşti, 407280, Romania

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Exelixis Clinical Site #127

Ploieşti, 100337, Romania

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Exelixis Clinical Site #143

Timișoara, 300239, Romania

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Exelixis Clinical Site #23

Košice, 04191, Slovakia

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Exelixis Clinical Site #27

Trnava, 91775, Slovakia

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Exelixis Clinical Site #121

Žilina, 01207, Slovakia

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Exelixis Clinical Site #7

Busan, Gangwon-do, 49267, South Korea

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Exelixis Clinical Site #30

Suwon, Gyeonggi-do, 16247, South Korea

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Exelixis Clinical Site #17

Suwon, Gyeonggi-do, 16499, South Korea

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Exelixis Clinical Site #9

Yangsan, Gyeongsangnam-do, 50612, South Korea

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Exelixis Clinical Site #69

Jeonju, Jeollabuk-do, 54907, South Korea

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Exelixis Clinical Site #8

Jeonju, Jeollabuk-do, 54907, South Korea

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Exelixis Clinical Site #13

Busan, 49201, South Korea

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Exelixis Clinical Site #5

Seoul, 3722, South Korea

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Exelixis Clinical Site #63

Seoul, 5505, South Korea

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Exelixis Clinical Site #12

Seoul, 6273, South Korea

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Exelixis Clinical Site #6

Seoul, 6591, South Korea

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Exelixis Clinical Site #29

Seoul, 8308, South Korea

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Exelixis Clinical Site #130

A Coruña, 15009, Spain

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Exelixis Clinical Site #115

Barcelona, 08025, Spain

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Exelixis Clinical Site #113

Girona, 17007, Spain

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Exelixis Clinical Site #134

Madrid, 28027, Spain

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Exelixis Clinical Site #111

Madrid, 28033, Spain

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Exelixis Clinical Site #32

Madrid, 28034, Spain

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Exelixis Clinical Site #59

Madrid, 28040, Spain

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Exelixis Clinical Site #31

Madrid, 28046, Spain

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Exelixis Clinical Site #136

Pamplona, 31008, Spain

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Exelixis Clinical Site #126

Seville, 41009, Spain

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Exelixis Clinical Site #153

Valencia, 46009, Spain

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Exelixis Clinical Site #41

Zaragoza, 50009, Spain

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Exelixis Clinical Site #145

Kaohsiung City, 807, Taiwan

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Exelixis Clinical Site #164

Taichung, 40447, Taiwan

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Exelixis Clinical Site #118

Taipei, 100229, Taiwan

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Exelixis Clinical Site #142

Taipei, 11217, Taiwan

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Exelixis Clinical Site #165

Taoyuan District, 33305, Taiwan

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Exelixis Clinical Site #71

Bangkoknoi, Bangkok, 10700, Thailand

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Exelixis Clinical Site #79

Hat Yai, Changwat Songkhla, 90110, Thailand

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Exelixis Clinical Site #56

Chiang Mai, Chiang Mai, 50200, Thailand

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Exelixis Clinical Site #80

Bangkok, 10330, Thailand

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Exelixis Clinical Site #135

London, England, SW36JJ, United Kingdom

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Exelixis Clinical Site #84

Romford, Essex, RM7 0AG, United Kingdom

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Exelixis Clinical Site #138

Manchester, M20 4BX, United Kingdom

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Exelixis Clinical Site #133

Sutton, SM2 5PT, United Kingdom

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Exelixis Clinical Site #161

Torquay, TQ2 7AA, United Kingdom

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Related Publications (1)

• Saba NF, Harrington K, Licitra L, Machiels JP, He C, Jew T, Andrianov V, Haddad R. STELLAR-305: phase II/III study of zanzalintinib plus pembrolizumab versus pembrolizumab alone in patients with HNSCC. Future Oncol. 2025 May;21(11):1349-1356. doi: 10.1080/14796694.2025.2485015. Epub 2025 Apr 18.

  PMID: 40248950 DERIVED

MeSH Terms

Conditions

Squamous Cell Carcinoma of Head and Neck

Interventions

pembrolizumab

Condition Hierarchy (Ancestors)

Carcinoma, Squamous Cell; Carcinoma; Neoplasms, Glandular and Epithelial; Neoplasms by Histologic Type; Neoplasms; Head and Neck Neoplasms; Neoplasms by Site

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: October 9, 2023
• First Posted: October 13, 2023
• Study Start: June 7, 2024
• Primary Completion (Estimated): August 1, 2028
• Study Completion (Estimated): March 1, 2029
• Last Updated: August 17, 2025

Record last verified: 2025-08

Data Sharing

• IPD Sharing: Will not share

Locations

PL (3); AR (8); AU (5); HU (4); SL (3); KR (12); TW (5); GB (5); US (15); DE (1); BE (4); ME (3); RO (6); GR (6); CO (5); ES (12); BR (16); IL (5); TH (4); IT (9); BU (5); FR (13); MY (3); CL (7); CZ (6)