Squamous Cell Carcinoma of Head and Neck
Conditions
Keywords
Programmed Cell Death-1 (PD1, PD-1), Programmed Death-Ligand 1 (PDL1, PD-L1)
Brief summary
Researchers are looking for new ways to treat people with head and neck cancer whose cancer has come back after treatment (recurrent) or whose cancer has spread to other parts of the body (metastatic). Some people with recurrent or metastatic head and neck cancer are treated with chemotherapy and immunotherapy, but the cancer gets worse. The goal of this study is to learn if more people who receive lenvatinib and pembrolizumab have a better overall survival rate than people who receive standard chemotherapy treatment.
Detailed description
With Amendment 7, participants will discontinue lenvatinib and pembrolizumab and lenvatinib monotherapy, unless discussed with the Sponsor. A protocol-specified periodic safety review was completed with a data cut-off of 31-May-2024 (Primary Completion Date) and served as the final analysis of the primary outcome measure. Per protocol, 34 participants enrolled after the primary completion date and will be analyzed in the End of Trial analysis.
Interventions
DRUGLenvatinib
20 mg once daily, taken as oral capsules
BIOLOGICALPembrolizumab
200 mg 30-minute IV infusion on day 1 of each 21-day cycle
DRUGDocetaxel
75 mg/m\^2 administered as an IV infusion on day 1 of each 21-day cycle
DRUGCapecitabine
1250 mg/m\^2 twice daily on days 1-14 of each 21-day cycle, taken as oral tablets
DRUGPaclitaxel
80 mg/m\^2 administered as an IV infusion on days 1, 8, and 15 of each 21-day cycle
DRUGCetuximab
400 mg/m\^2 loading dose, followed by 250 mg/m\^2 administered as an IV infusion on days 1, 8, and 15 of each 21-day cycle
Sponsors
Eisai Inc.
Merck Sharp & Dohme LLC
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
SINGLE (Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Pathologically confirmed recurrent (not amenable to curative treatment with local and/or systemic therapies) or metastatic (disseminated) head and neck squamous cell carcinoma (HNSCC) of the oral cavity, oropharynx, hypopharynx, and/or larynx that is considered incurable by local therapies * Disease progression at any time during or after treatment with a platinum-containing (e.g., carboplatin or cisplatin) regimen * Disease progression on or after treatment with a programmed cell death protein 1/programmed death-ligand 1 monoclonal antibody (anti-PD-1/PD-L1 mAb) * Pre-study imaging that demonstrates evidence of disease progression based on investigator review of at least 2 pre-study images per RECIST 1.1, following initiation of treatment with a PD-1/PD-L1 inhibitor * Measurable disease by computed tomography scan (CT) or magnetic resonance imaging (MRI) based on Response Criteria in Solid Tumors Version 1.1 (RECIST 1.1) as verified by blinded independent central review (BICR). Tumor lesions situated in a previously irradiated area are considered measurable if progression has been demonstrated in such lesions * Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 assessed within 7 days of the first dose of study intervention * Male participants are eligible to participate if they agree to the following during the intervention period and for at least 1 week after the last dose of lenvatinib, 3 months after the last dose of capecitabine and paclitaxel, and 6 months after the last dose of docetaxel: * Refrain from donating sperm * Be abstinent from heterosexual intercourse as their preferred and usual lifestyle (abstinent on a long term and persistent basis) and agree to remain abstinent; or must agree to use contraception unless confirmed to be azoospermic * Contraceptive use by men should be consistent with local regulations regarding the methods of contraception for those participating in clinical studies * A female participant is eligible to participate if she is not pregnant or breastfeeding, and at least one of the following conditions applies: * Is not a woman of childbearing potential (WOCBP) * Is a WOCBP and using a contraceptive method that is highly effective (with a failure rate of \<1% per year), with low user dependency or be abstinent from heterosexual intercourse as their preferred and usual lifestyle (abstinent on a long term and persistent basis), during the intervention period and for at least 120 days post pembrolizumab or 1 month post lenvatinib, whichever occurs last (Arms 1 and 3), or during the intervention period and for at least 6 months after the last dose of capecitabine, docetaxel, paclitaxel; and 2 months after the last dose of cetuximab (Arm 2) * Female participants who randomize to Arm 2 must also agree not to donate or freeze/store eggs during the intervention period and for at least 6 months after the last dose of capecitabine, docetaxel, paclitaxel; and 2 months after the last dose of cetuximab * Adequately controlled blood pressure (BP) with or without antihypertensive medications * Participants who are hepatitis B surface antigen (HBsAg) positive are eligible if they have received hepatitis B virus (HBV) antiviral therapy for at least 4 weeks and have undetectable HBV viral load prior to randomization * Participants with history of hepatitis C virus (HCV) infection are eligible if HCV viral load is undetectable at screening * Adequate organ function
Exclusion criteria
* Disease that is suitable for local therapy administered with curative intent * Life expectancy of less than 3 months and/or has rapidly progressing disease in the opinion of the treating investigator * History of (noninfectious) pneumonitis/interstitial lung disease that required steroids, or has current pneumonitis/interstitial lung disease * Active infection requiring systemic therapy * 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 to the first dose of study drug * Known active central nervous system (CNS) metastases and/or carcinomatous meningitis * Known additional malignancy that is progressing or has required active systemic treatment within the past 3 years, except basal cell carcinoma of the skin, squamous cell carcinoma of the skin, superficial bladder cancer, or carcinoma in situ that have undergone potentially curative therapy * Active autoimmune disease that has required systemic treatment in the past 2 years * Had an allogeneic tissue/solid organ transplant * Known history of human immunodeficiency virus (HIV) infection * History of any contraindication or has a severe hypersensitivity to any components of pembrolizumab, lenvatinib or SOC chemotherapy. * Pre-existing ≥Grade 3 gastrointestinal or non-gastrointestinal fistula * History of a gastrointestinal malabsorption or any other condition or procedure that may affect oral study drug absorption * Had major surgery within 3 weeks prior to first dose of study interventions * Clinically significant cardiovascular impairment within 12 months of the first dose of study drug * Active tuberculosis * Has difficulty swallowing capsules or ingesting a suspension orally, or by a feeding tube * Prior treatment with lenvatinib * Prior chemotherapy, targeted small molecule therapy, or radiation therapy within 2 weeks prior to Study Day 1 or has not recovered from adverse events (AEs) due to a previously administered agent. Participants with endocrine-related AEs Grade ≤2 requiring treatment or hormone replacement may be eligible * Has received a live or live attenuated vaccine within 30 days prior to the first dose of study intervention. Note: Administration of killed vaccines is allowed * Previously treated with 4 or more systemic regimens given for recurrent/metastatic disease * Has received an investigational agent or has used an investigational device within 4 weeks prior to study intervention administration * 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 |
|---|---|---|
| Overall Survival (OS) | Up to approximately 45 months | OS was defined as the time from randomization to death due to any cause. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Progression-Free Survival (PFS) | Up to approximately 45 months | PFS was defined as the time from randomization to the first documented progressive disease (PD) or death due to any cause, whichever occurred first. Responses were according to modified Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 as assessed by blinded independent central review (BICR). RECIST 1.1 was modified to follow a maximum of 10 target lesions and a maximum of 5 target lesions per organ. 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 have demonstrated an absolute increase of ≥5 mm. Note: The appearance of one or more new lesions was also considered PD. |
| Objective Response Rate (ORR) | Up to approximately 45 months | ORR was defined as the percentage of participants who had a confirmed complete response (CR: disappearance of all target lesions) or partial response (PR: At least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum of the diameters of target lesions) until progressive disease (PD) or death due to any cause, whichever occurred first. Responses were according to modified RECIST 1.1 as assessed by BICR. RECIST 1.1 was modified to follow a maximum of 10 target lesions and a maximum of 5 target lesions per organ. |
| Duration of Response (DOR) | Up to approximately 45 months | DOR was defined as the time from the first documented evidence of complete response (CR: disappearance of all target lesions) or partial response (PR: At least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum of the diameters of target lesions) until progressive disease (PD) or death due to any cause, whichever occurred first. Responses were according to modified RECIST 1.1 as assessed by BICR. |
| Number of Participants Who Experienced One or More Adverse Events (AEs) | Up to approximately 5 years | An AE was any untoward medical occurrence in a participant, temporally associated with the use of study treatment, whether or not considered related to the study treatment. The number of participants who experience an AE was presented. |
| Number of Participants Who Discontinued Study Intervention Due to an Adverse Event (AE) | Up to approximately 5 years | An AE was any untoward medical occurrence in a participant, temporally associated with the use of study treatment, whether or not considered related to the study treatment. The number of participants who discontinue study treatment due to an AE was presented. |
Countries
Australia, Brazil, Canada, Colombia, Denmark, France, Israel, Norway, Portugal, Romania, South Korea, Spain, Taiwan, United Kingdom, United States
Participant flow
Pre-assignment details
Protocol-specified final analysis for the results, including participant flow, was performed on 374 participants enrolled within the primary completion data cut-off. Analysis of the remaining 34 participants will be included in the End of Trial analysis. Participants who experienced progressive disease in the lenvatinib monotherapy or Standard of Care arms could switch over to receive lenvatinib + pembrolizumab. One participant switched over and received only pembrolizumab.
Participants by arm
| Arm | Count |
|---|---|
| Lenvatinib + Pembrolizumab Participants were treated with the combination of lenvatinib (once daily 20 mg oral dose) plus pembrolizumab (200 mg 30-minute intravenous (IV) infusion on Day 1 of each 21-day cycle for 35 cycles), until centrally verified disease progression, or until a protocol-specified discontinuation criterion was met. | 144 |
| SOC Chemotherapy Participants were treated with investigator's choice of standard of care (SOC) chemotherapy (docetaxel, paclitaxel, cetuximab, or capecitabine) until centrally verified disease progression, or until a protocol-specified discontinuation criterion was met. | 142 |
| Lenvatinib Monotherapy Participants were treated with lenvatinib monotherapy (once daily 24 mg oral dose) until centrally verified disease progression, or until a protocol-specified discontinuation criterion was met. | 88 |
| Total | 374 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | Death | 100 | 86 | 57 |
| Overall Study | Lost to Follow-up | 1 | 1 | 0 |
| Overall Study | Participant Ongoing in Study | 41 | 53 | 28 |
| Overall Study | Withdrawal by Subject | 2 | 2 | 3 |
Baseline characteristics
| Characteristic | Lenvatinib + Pembrolizumab | SOC Chemotherapy | Lenvatinib Monotherapy | Total |
|---|---|---|---|---|
| Age, Continuous | 62.3 Years STANDARD_DEVIATION 9 | 61.4 Years STANDARD_DEVIATION 10 | 59.9 Years STANDARD_DEVIATION 9.3 | 61.4 Years STANDARD_DEVIATION 9.5 |
| Eastern Cooperative Oncology Group (ECOG) Performance Status ECOG = 0 | 52 Participants | 58 Participants | 32 Participants | 142 Participants |
| Eastern Cooperative Oncology Group (ECOG) Performance Status ECOG = 1 | 92 Participants | 84 Participants | 56 Participants | 232 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 3 Participants | 3 Participants | 6 Participants | 12 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 139 Participants | 137 Participants | 82 Participants | 358 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 2 Participants | 2 Participants | 0 Participants | 4 Participants |
| Programmed Cell Death Ligand 1 (PD-L1) Status at Baseline TPS = <50% | 121 Participants | 120 Participants | 74 Participants | 315 Participants |
| Programmed Cell Death Ligand 1 (PD-L1) Status at Baseline TPS = ≥ 50% | 23 Participants | 22 Participants | 14 Participants | 59 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 1 Participants | 2 Participants | 3 Participants | 6 Participants |
| Race (NIH/OMB) Asian | 35 Participants | 40 Participants | 25 Participants | 100 Participants |
| Race (NIH/OMB) Black or African American | 2 Participants | 4 Participants | 2 Participants | 8 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 2 Participants | 0 Participants | 1 Participants | 3 Participants |
| Race (NIH/OMB) White | 104 Participants | 96 Participants | 57 Participants | 257 Participants |
| Sex: Female, Male Female | 18 Participants | 19 Participants | 14 Participants | 51 Participants |
| Sex: Female, Male Male | 126 Participants | 123 Participants | 74 Participants | 323 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk | EG005 affected / at risk |
|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 103 / 144 | 42 / 142 | 50 / 88 | 44 / 61 | 1 / 1 | 10 / 18 |
| other Total, other adverse events | 139 / 143 | 135 / 140 | 80 / 88 | 55 / 61 | 1 / 1 | 15 / 18 |
| serious Total, serious adverse events | 86 / 143 | 57 / 140 | 45 / 88 | 27 / 61 | 1 / 1 | 6 / 18 |
Outcome results
Primary
Overall Survival (OS)
OS was defined as the time from randomization to death due to any cause.
Time frame: Up to approximately 45 months
Population: The analysis population consisted of all participants who were randomized prior to the primary completion data cut-off. Per protocol, participants who received lenvatinib monotherapy were not analyzed.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Lenvatinib + Pembrolizumab | Overall Survival (OS) | 8.4 Months |
| SOC Chemotherapy | Overall Survival (OS) | 11.3 Months |
p-value: 0.996395% CI: [1.11, 1.97]Log Rank
Secondary
Duration of Response (DOR)
DOR was defined as the time from the first documented evidence of complete response (CR: disappearance of all target lesions) or partial response (PR: At least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum of the diameters of target lesions) until progressive disease (PD) or death due to any cause, whichever occurred first. Responses were according to modified RECIST 1.1 as assessed by BICR.
Time frame: Up to approximately 45 months
Population: The analysis population consisted of all participants randomized by the primary completion data cut-off who experienced a confirmed CR or PR. Per protocol, participants who received lenvatinib monotherapy were not analyzed.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Lenvatinib + Pembrolizumab | Duration of Response (DOR) | 4.1 Months |
| SOC Chemotherapy | Duration of Response (DOR) | 5.9 Months |
Secondary
Number of Participants Who Discontinued Study Intervention Due to an Adverse Event (AE)
An AE was any untoward medical occurrence in a participant, temporally associated with the use of study treatment, whether or not considered related to the study treatment. The number of participants who discontinue study treatment due to an AE was presented.
Time frame: Up to approximately 5 years
Secondary
Number of Participants Who Experienced One or More Adverse Events (AEs)
An AE was any untoward medical occurrence in a participant, temporally associated with the use of study treatment, whether or not considered related to the study treatment. The number of participants who experience an AE was presented.
Time frame: Up to approximately 5 years
Secondary
Objective Response Rate (ORR)
ORR was defined as the percentage of participants who had a confirmed complete response (CR: disappearance of all target lesions) or partial response (PR: At least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum of the diameters of target lesions) until progressive disease (PD) or death due to any cause, whichever occurred first. Responses were according to modified RECIST 1.1 as assessed by BICR. RECIST 1.1 was modified to follow a maximum of 10 target lesions and a maximum of 5 target lesions per organ.
Time frame: Up to approximately 45 months
Population: The analysis population consisted of all participants randomized by the primary completion data cut-off. Per protocol, participants who received lenvatinib monotherapy were not analyzed.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Lenvatinib + Pembrolizumab | Objective Response Rate (ORR) | 13.9 Percentage of Participants |
| SOC Chemotherapy | Objective Response Rate (ORR) | 20.4 Percentage of Participants |
p-value: 0.926621995% CI: [-15.4, 2.3]Miettinen & Nurminen
Secondary
Progression-Free Survival (PFS)
PFS was defined as the time from randomization to the first documented progressive disease (PD) or death due to any cause, whichever occurred first. Responses were according to modified Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 as assessed by blinded independent central review (BICR). RECIST 1.1 was modified to follow a maximum of 10 target lesions and a maximum of 5 target lesions per organ. 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 have demonstrated an absolute increase of ≥5 mm. Note: The appearance of one or more new lesions was also considered PD.
Time frame: Up to approximately 45 months
Population: The analysis population consisted of all participants randomized by the primary completion data cut-off. Per protocol, participants who received lenvatinib monotherapy were not analyzed.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Lenvatinib + Pembrolizumab | Progression-Free Survival (PFS) | 3.0 Months |
| SOC Chemotherapy | Progression-Free Survival (PFS) | 2.8 Months |
p-value: 0.418195% CI: [0.74, 1.28]Log Rank