Head and Neck Squamous Cell Carcinoma
Conditions
Keywords
head and neck squamous cell carcinoma, pembrolizumab, lenvatinib, PD-L1
Brief summary
This is a study of pembrolizumab (MK-3475) with or without lenvatinib (E7080/MK-7902) as a first line intervention in a PD-L1 selected population with participants with recurrent or metastatic head and neck squamous cell carcinoma. Hypotheses include: * Pembrolizumab + lenvatinib is superior to pembrolizumab + placebo with respect to Objective Response Rate (ORR) per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) by blinded independent central review (BICR). * Pembrolizumab + lenvatinib is superior to pembrolizumab + placebo with respect to Progression Free Survival (PFS) per RECIST 1.1 as assessed by BICR. * Pembrolizumab + lenvatinib is superior to pembrolizumab + placebo with respect to overall survival (OS).
Detailed description
The MK-7902-010-China Extension Study will include participants previously enrolled in China in the global study for MK-7902-010 (NCT04199104) plus those enrolled during the China extension enrollment period.
Interventions
BIOLOGICALPembrolizumab
Pembrolizumab (MK-3475), 200 mg, every 3 weeks (Q3W) by intravenous (IV) infusion for up to 35 3-week cycles
DRUGLenvatinib
Lenvatinib, 20 mg (two 10-mg oral capsules) administered QD
DRUGPlacebo
Lenvatinib-matching placebo, oral capsules, administered once daily (QD)
Sponsors
Merck Sharp & Dohme LLC
Eisai Inc.
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Masking description
Study was unblinded on August 16, 2023
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Has histologically confirmed diagnosis of recurrent/metastatic head and neck squamous cell carcinoma (R/M HNSCC) that is considered incurable by local therapies Note: Participants with newly-diagnosed HNSCC must be M1/Stage IV * Has a primary tumor location of oropharynx, oral cavity, hypopharynx, or larynx Note: Primary tumor site of nasopharynx (any histology) or unknown primary tumor (including p16+ unknown primary) are not eligible Contraceptive use by men should be consistent with local regulations regarding the methods of contraception for those participating in clinical studies. If the contraception requirements in the local label for any of the study interventions is more stringent than the requirements above, the local label requirements are to be followed * Male participants agree to use approved contraception during the treatment period for at least 7 days after the last dose of lenvatinib/placebo, or refrain from heterosexual intercourse during this period * Female participants are not pregnant or breastfeeding, and are not a woman of childbearing potential (WOCBP), OR are a WOCBP that agrees to use contraception during the treatment period (or 14 days prior to the initiation of study treatment for oral contraception) and for at least 120 days post pembrolizumab, or 30 days post lenvatinib/placebo, whichever occurs last * Has measurable disease per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) as assessed by blinded independent central review (BICR) Note: Lesions situated in a previously irradiated area are considered measurable if progression has been showed in such lesions * Participants with oropharyngeal cancer must have results from testing of human papillomavirus (HPV) status * Has an Eastern Cooperative Oncology Group (ECOG) performance score of 0 to 1 * Has adequately controlled blood pressure with or without antihypertensive medications * Has adequate organ function
Exclusion criteria
* Has any evidence of symptoms or signs of active tumor bleeding within 6 months before randomization * Has radiographic evidence of major blood vessel invasion/infiltration or tumor demonstrates \>90 degree abutment or encasement of a major blood vessel Note: The degree of proximity to major blood vessels should be considered because of the potential risk of severe hemorrhage associated with tumor shrinkage/necrosis after lenvatinib therapy * Has a history of re-irradiation to any head and neck sites of disease including the cervical, infraclavicular or supraclavicular lymph nodes for head and neck cancer * Has ulceration and/or fungation of disease onto the skin surface * Has a history of any contraindication or has a severe hypersensitivity to any components of pembrolizumab (≥Grade 3) or lenvatinib * Has pre-existing ≥Grade 3 gastrointestinal or non-gastrointestinal fistula * Has a history of a gastrointestinal condition or procedure that, in the opinion of the investigator, may affect oral study drug absorption * Has clinically significant cardiovascular impairment within 12 months of the first dose of study intervention, such as history of congestive heart failure greater than New York Heart Association (NYHA) Class II, unstable angina, myocardial infarction or cerebrovascular accident/transient ischemic attack (TIA)/stroke, cardiac revascularization, or cardiac arrhythmia associated with hemodynamic instability * Has disease that is suitable for local therapy administered with curative intent * Had PD within 6 months of completion of curatively intended systemic treatment for locoregionally advanced HNSCC * Has had major surgery within 3 weeks before to first dose of study interventions * Has difficulty swallowing capsules or ingesting a suspension orally or by a feeding tube * Has received prior therapy with lenvatinib or pembrolizumab * Received last dose of systemic therapy for locoregionally advanced disease less than 6 months before signing consent * Has received prior therapy with an anti-programmed cell death 1 protein (anti-PD-1), anti-programmed cell death ligand 1 (anti-PD-L1), or anti-programmed cell death ligand 2 (anti PD-L2) agent or with an agent directed to another stimulatory or co-inhibitory T-cell receptor (e.g., CTLA-4, OX-40, CD137) * Has received prior systemic anticancer therapy including investigational agents within 4 weeks before randomization * Has received prior radiotherapy within 2 weeks of start of study intervention * Has received a live vaccine within 30 days before the first dose of study intervention. Administration of killed vaccines is allowed * Has received an investigational agent or has used an investigational device within 4 weeks prior to study intervention-administration * Has a diagnosis of immunodeficiency or is receiving chronic systemic steroid therapy (in dosing exceeding 10 mg daily of prednisone equivalent) or any other form of immunosuppressive therapy within 7 days prior the first dose of study intervention * Has a known additional malignancy that is progressing or has required active treatment within the past 3 years Note: Participants with basal cell carcinoma of the skin, squamous cell carcinoma of the skin, or carcinoma in situ (e.g., breast carcinoma, cervical cancer in situ) that have undergone potentially curative therapy are not excluded * Has known active central nervous system (CNS) metastases and/or carcinomatous meningitis * Has an active autoimmune disease that has required systemic treatment in past 2 years. Replacement therapy (e.g., thyroxine, insulin, or physiologic corticosteroid) is allowed * Has a history of (non-infectious) pneumonitis that required steroids or has current pneumonitis * Has an active infection requiring systemic therapy. (e.g., tuberculosis, known viral or bacterial infections, etc.) * Has a known history of human immunodeficiency virus (HIV) infection * Has a known history of hepatitis B (defined as hepatitis B surface antigen \[HBsAg\] reactive) or known active hepatitis C virus (defined as HCV ribonucleic acid (RNA) \[qualitative\] is detected) infection * Is pregnant or breastfeeding or expecting to conceive or father children within the projected duration of the study, starting with the screening visit through 120 days after the last dose of study intervention * Has had an allogenic tissue/solid organ transplant * Has a known psychiatric or substance abuse disorder that would interfere with the participant's ability to cooperate with the requirements of the study
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Objective Response Rate (ORR) Per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) as Assessed by Blinded Independent Central Review (BICR) | Up to approximately 33 months | ORR was defined as the percentage of participants who have a Complete Response (CR: Disappearance of all target lesions) or a Partial Response (PR: At least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters) per RECIST 1.1 modified to follow a maximum of 10 target lesions and a maximum of 5 target lesions per organ. The percentage of participants who experienced a CR or PR based on modified RECIST 1.1 were reported. |
| Progression Free Survival (PFS) Per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) as Assessed by Blinded Independent Central Review (BICR) | Up to approximately 33 months | PFS was defined as the time from randomization to the first documented progressive disease (PD) or death due to any cause, whichever occurs first. Per RECIST 1.1, PD was defined as ≥20% increase in the sum of diameters of target lesions. In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of ≥5 mm. The appearance of one or more new lesions was also considered PD. |
| Overall Survival (OS) | Up to approximately 33 months | OS was the time from randomization to death due to any cause. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Duration of Response (DOR) | Up to approximately 33 months | For participants who demonstrate a confirmed complete response (CR: Disappearance of all target lesions) or confirmed Partial Response (PR: At least a 30% decrease in the sum of diameters of target lesions) per RECIST 1.1, DOR is defined as the time from first documented evidence of CR or PR until disease progression or death. |
| Number of Participants Who Experienced an Adverse Event (AE) | Up to approximately 52 months | An adverse event (AE) was defined as any unfavorable and unintended sign including an abnormal laboratory finding, symptom or disease associated with the use of a medical treatment or procedure, regardless of whether it is considered related to the medical treatment or procedure, that occurs during the course of the study. Number of participants who experienced an AE will be reported. |
| Number of Participants Who Discontinued Study Drug Due to an AE | Up to approximately 34 months | An adverse event (AE) is defined as any unfavorable and unintended sign including an abnormal laboratory finding, symptom or disease associated with the use of a medical treatment or procedure, regardless of whether it is considered related to the medical treatment or procedure, that occurs during the course of the study. |
Countries
China
Contacts
STUDY_DIRECTORMedical Director
Merck Sharp & Dohme LLC
Participant flow
Recruitment details
A total of 112 Chinese participants were randomized in the China extension study. Of 112 Chinese participants, 57 participants were randomized in the global portion of the MK-7902-010 (NCT04199104) study and 55 participants were randomized in the China extension portion.
Participants by arm
| Arm | Count |
|---|---|
| Pembrolizumab + Lenvatinib Participants received lenvatinib 20 mg orally once a day (QD) plus pembrolizumab 200 mg by intravenous (IV) infusion on Day 1 of each 21-day cycle (Q3W). Pembrolizumab will be administered for up to 35 cycles (approximately 24 months). Per Amendment (AM) 5, (effective date: 16-Aug-2023), participants discontinued lenvatinib and participants who remained on treatment received open-label pembrolizumab only. Eligible participants who completed the first course of up to 35 administrations of pembrolizumab (\
2 years) or who attained complete response (CR) but experienced progression of disease (PD), initiated a second course of pembrolizumab at the investigator's discretion, at the same dose and schedule at 200 mg IV on Day 1 each 3-week cycle (Q3W), for up to 17 cycles (up to \
1 year). | 61 |
| Pembrolizumab + Placebo Participants received lenvatinib-matching placebo orally once a day (QD) plus pembrolizumab 200 mg by IV infusion on Day 1 of each 3-week cycle for up to 35 cycles (approximately 24 months). Per Amendment (AM) 5, (effective date: 16-Aug-2023), participants discontinued placebo and participants who remained on treatment received open-label pembrolizumab only. Eligible participants who completed the first course of up to 35 administrations of pembrolizumab (\
2 years) or who attained complete response (CR) but experienced progression of disease (PD), initiated a second course of pembrolizumab at the investigator's discretion, at the same dose and schedule at 200 mg IV on Day 1 each 3-week cycle (Q3W), for up to 17 cycles (up to \
1 year). | 51 |
| Total | 112 |
Baseline characteristics
| Characteristic | Pembrolizumab + Placebo | Total | Pembrolizumab + Lenvatinib |
|---|---|---|---|
| Age, Continuous | 58.4 Years STANDARD_DEVIATION 11 | 59.2 Years STANDARD_DEVIATION 10.1 | 59.9 Years STANDARD_DEVIATION 9.4 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 0 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 45 Participants | 101 Participants | 56 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 6 Participants | 11 Participants | 5 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 51 Participants | 112 Participants | 61 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 0 Participants | 0 Participants | 0 Participants |
| Sex: Female, Male Female | 3 Participants | 12 Participants | 9 Participants |
| Sex: Female, Male Male | 48 Participants | 100 Participants | 52 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 41 / 61 | 43 / 51 |
| other Total, other adverse events | 59 / 61 | 45 / 50 |
| serious Total, serious adverse events | 34 / 61 | 19 / 50 |
Outcome results
Primary
Objective Response Rate (ORR) Per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) as Assessed by Blinded Independent Central Review (BICR)
ORR was defined as the percentage of participants who have a Complete Response (CR: Disappearance of all target lesions) or a Partial Response (PR: At least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters) per RECIST 1.1 modified to follow a maximum of 10 target lesions and a maximum of 5 target lesions per organ. The percentage of participants who experienced a CR or PR based on modified RECIST 1.1 were reported.
Time frame: Up to approximately 33 months
Population: All randomized Chinese participants
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Pembrolizumab + Lenvatinib | Objective Response Rate (ORR) Per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) as Assessed by Blinded Independent Central Review (BICR) | 39.3 Percentage of participants |
| Pembrolizumab + Placebo | Objective Response Rate (ORR) Per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) as Assessed by Blinded Independent Central Review (BICR) | 9.8 Percentage of participants |
p-value: 0.000201495% CI: [14, 43.9]Unstratified Miettinen & Nurminen method
Primary
Overall Survival (OS)
OS was the time from randomization to death due to any cause.
Time frame: Up to approximately 33 months
Population: All randomized Chinese participants
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Pembrolizumab + Lenvatinib | Overall Survival (OS) | 10.9 Months |
| Pembrolizumab + Placebo | Overall Survival (OS) | 11.9 Months |
p-value: 0.3093395% CI: [0.49, 1.54]Unstratified Log-rank test
Primary
Progression Free Survival (PFS) Per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) as Assessed by Blinded Independent Central Review (BICR)
PFS was defined as the time from randomization to the first documented progressive disease (PD) or death due to any cause, whichever occurs first. Per RECIST 1.1, PD was defined as ≥20% increase in the sum of diameters of target lesions. In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of ≥5 mm. The appearance of one or more new lesions was also considered PD.
Time frame: Up to approximately 33 months
Population: All randomized Chinese participants.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Pembrolizumab + Lenvatinib | Progression Free Survival (PFS) Per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) as Assessed by Blinded Independent Central Review (BICR) | 7.0 Months |
| Pembrolizumab + Placebo | Progression Free Survival (PFS) Per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) as Assessed by Blinded Independent Central Review (BICR) | 1.5 Months |
p-value: 0.000003795% CI: [0.21, 0.55]unstratified Log-rank test.
Secondary
Duration of Response (DOR)
For participants who demonstrate a confirmed complete response (CR: Disappearance of all target lesions) or confirmed Partial Response (PR: At least a 30% decrease in the sum of diameters of target lesions) per RECIST 1.1, DOR is defined as the time from first documented evidence of CR or PR until disease progression or death.
Time frame: Up to approximately 33 months
Population: All randomized Chinese participants with a confirmed CR or PR.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Pembrolizumab + Lenvatinib | Duration of Response (DOR) | 8.3 Months |
| Pembrolizumab + Placebo | Duration of Response (DOR) | NA Months |
Secondary
Number of Participants Who Discontinued Study Drug Due to an AE
An adverse event (AE) is defined as any unfavorable and unintended sign including an abnormal laboratory finding, symptom or disease associated with the use of a medical treatment or procedure, regardless of whether it is considered related to the medical treatment or procedure, that occurs during the course of the study.
Time frame: Up to approximately 52 months
Secondary
Number of Participants Who Experienced an Adverse Event (AE)
An adverse event (AE) was defined as any unfavorable and unintended sign including an abnormal laboratory finding, symptom or disease associated with the use of a medical treatment or procedure, regardless of whether it is considered related to the medical treatment or procedure, that occurs during the course of the study. Number of participants who experienced an AE will be reported.
Time frame: Up to approximately 52 months