Head and Neck Cancer
Conditions
Brief summary
The main purpose of this study is to compare nivolumab and ipilimumab with the extreme regimen as first line treatment in patients with recurrent or metastatic squamous cell of the head and neck cancer
Interventions
BIOLOGICALNivolumab
BIOLOGICALIpilimumab
DRUGCetuximab/Erbitux
DRUGCisplatin/Platinol
DRUGCarboplatin/Paraplatin
DRUGFluorouracil/Adrucil
Sponsors
Ono Pharmaceutical Co. Ltd
Bristol-Myers Squibb
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Histologically confirmed metastatic or recurrent squamous cell carcinoma of the head and neck (oral cavity, oropharynx, hypopharynx & larynx) that is not amenable to curative therapy. * No prior systemic cancer therapy for recurrent or metastatic disease (except if chemotherapy was part of multimodal treatment completed 6 months prior to enrolment). * Measurable disease detected by imaging exam (CT or MRI). * Have tumor tissue for PD L1 expression testing, and for oropharyngeal cancer have results from testing of HPV p16 status.
Exclusion criteria
* Metastatic or recurrent carcinoma of the nasopharynx, squamous cell carcinoma of unknown primary, squamous cell carcinoma originating from skin and salivary glands or non squamous histologies (eg. mucosal melanoma). * No prior treatment with anti PD1, anti PD L1, anti CTLA 4 antibody or any other antibody or drugs targeting T cell costimulation or checkpoint pathways, or cetuximab or EGFR inhibitors in any treatment setting. * Participants with certain diseases such as active autoimmune disease, type I diabetes, hypothyroidism that needs hormone replacement, active infection, psychiatric disorder. * Inadequate hematologic, renal or hepatic function. Other protocol defined inclusion/
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Overall Survival (OS) in Participants With Programmed Death-Ligand 1 (PD-L1) With a Combined Positive Score (CPS) ≥20 | From randomization to date of death or date the participant was last known to be alive (Up to approximately 55 months) | Overall survival (OS) is defined as the time between randomization and death. For participants without documentation of death, OS will be censored on the last date the participant was known to be alive. Overall survival will be censored at the date of randomization for participants who were randomized but had no follow-up. Survival follow-up will be conducted every 3 months after participants off-treatment date. (Based on Kaplan-Meier estimates) |
| Overall Survival (OS) in All Randomized Participants | From randomization to date of death or date the participant was last known to be alive (Up to approximately 55 months) | Overall survival (OS) is defined as the time between randomization and death. For participants without documentation of death, OS will be censored on the last date the participant was known to be alive. Overall survival will be censored at the date of randomization for participants who were randomized but had no follow-up. Survival follow-up will be conducted every 3 months after participants off-treatment date. (Based on Kaplan-Meier estimates) |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Overall Survival (OS) in Randomized Participants With Programmed Death-Ligand 1 (PD-L1) With a Combined Positive Score (CPS) ≥ 1 | From randomization to date of death or date the participant was last known to be alive (Up to approximately 65 months) | Overall survival (OS) is defined as the time between randomization and death. For participants without documentation of death, OS will be censored on the last date the participant was known to be alive. Overall survival will be censored at the date of randomization for participants who were randomized but had no follow-up. Survival follow-up will be conducted every 3 months after participants off-treatment date. (Based on Kaplan-Meier estimates) |
| Progression Free Survival (PFS) | From randomization to disease progression or death (Up to approximately 65 months) | PFS is defined as the time between the date of randomization and the date of first documented tumor progression, based on Blinded Independent Central Review (BICR) assessments (per Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 criteria), or death due to any cause, whichever occurs first. Participants who neither progress nor die will be censored on the date of their last tumor assessment. Participants who receive subsequent anti-cancer therapy prior to documented progression, will be censored on the date of their last tumor assessment prior to subsequent therapy. (Based on Kaplan-Meier Estimates) Progression is defined as at least a 20% increase in the sum of diameters of target lesions, in addition the sum must also demonstrate an absolute increase of at least 5 mm. (Note: the appearance of one or more new lesions is also considered progression). |
| Objective Response Rate (ORR) | From randomization up to approximately 65 months | Objective Response Rate (ORR) is defined as the number of participants with a best overall response (BOR) of complete response (CR) or partial response (PR). Based on Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 criteria by blinded independent central review (BICR) assessment. Complete Response (CR): Disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to \< 10 mm. Partial Response (PR): At least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters. |
| Duration of Objective Response (DOR) | From randomization to the first documented response (CR or PR) and progression (up to approximately 65 months) | The time between the first documented response (Complete response (CR) or partial response (PR)) and progression or death, per RECIST 1.1 by blinded independent central review (BICR) assessment. (Based on Kaplan-Meier Estimates) Complete Response (CR): Disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to \< 10 mm. Partial Response (PR): At least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters. |
Countries
Australia, Austria, Brazil, France, Germany, Greece, Ireland, Israel, Italy, Japan, Mexico, Poland, South Korea, Spain, Switzerland, Taiwan, United Kingdom, United States
Participant flow
Pre-assignment details
947 participants randomized to receive study treatment. 909 participants received study treatment.
Participants by arm
| Arm | Count |
|---|---|
| Nivolumab + Ipilimumab Nivolumab 3 mg/kg IV every 2 weeks + Ipilimumab 1 mg/kg IV every 6 weeks until progression, unacceptable toxicity, or a maximum of 24 months from first nivolumab treatment. | 472 |
| EXTREME Regimen Cetuximab 400 mg/m2 IV for the initial dose only, then 250 mg/m2 weekly + cisplatin (100mg/m2) or carboplatin (AUC of 5 mg per milliliter per minute) on Day 1 and fluorouracil (1000 mg/m2 per day for 4 days) every 3 weeks for maximum of 6 cycles followed by maintenance cetuximab at 250 mg/m2 weekly (or every 2 weeks, per local prescribing information) until disease progression or unacceptable toxicity; the choice of cisplatin or carboplatin is at the discretion of the investigator. | 475 |
| Total | 947 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Pre-Treatment Period | Adverse event unrelated to study drug | 1 | 0 |
| Pre-Treatment Period | Death | 0 | 1 |
| Pre-Treatment Period | Disease progression | 0 | 1 |
| Pre-Treatment Period | Lost to Follow-up | 0 | 2 |
| Pre-Treatment Period | Other reasons | 0 | 3 |
| Pre-Treatment Period | Participant no longer meets study criteria | 3 | 6 |
| Pre-Treatment Period | Participant request to discontinue study treatment | 0 | 2 |
| Pre-Treatment Period | Participant withdrew consent | 0 | 18 |
| Pre-Treatment Period | Poor/non-compliance | 0 | 1 |
| Treatment Period | Administrative reason by sponsor | 0 | 1 |
| Treatment Period | Adverse event unrelated to study drug | 41 | 26 |
| Treatment Period | Death | 9 | 7 |
| Treatment Period | Disease progression | 294 | 301 |
| Treatment Period | Lost to Follow-up | 1 | 3 |
| Treatment Period | Maximum clinical benefit | 4 | 6 |
| Treatment Period | Other reasons | 47 | 12 |
| Treatment Period | Participant request to discontinue treatment | 8 | 23 |
| Treatment Period | Participant withdrew consent | 9 | 13 |
| Treatment Period | Poor/non-compliance | 0 | 2 |
| Treatment Period | Study drug toxicity | 55 | 47 |
Baseline characteristics
| Characteristic | Nivolumab + Ipilimumab | EXTREME Regimen | Total |
|---|---|---|---|
| Age, Continuous | 60.4 Years STANDARD_DEVIATION 9.7 | 60.9 Years STANDARD_DEVIATION 9.5 | 60.6 Years STANDARD_DEVIATION 9.6 |
| Age, Customized < 65 | 310 Participants | 295 Participants | 605 Participants |
| Age, Customized >= 65 AND < 75 | 134 Participants | 151 Participants | 285 Participants |
| Age, Customized >= 75 AND < 85 | 26 Participants | 28 Participants | 54 Participants |
| Age, Customized >= 85 | 2 Participants | 1 Participants | 3 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 40 Participants | 43 Participants | 83 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 199 Participants | 207 Participants | 406 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 233 Participants | 225 Participants | 458 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 7 Participants | 5 Participants | 12 Participants |
| Race (NIH/OMB) Asian | 58 Participants | 55 Participants | 113 Participants |
| Race (NIH/OMB) Black or African American | 15 Participants | 7 Participants | 22 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 1 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 12 Participants | 7 Participants | 19 Participants |
| Race (NIH/OMB) White | 379 Participants | 401 Participants | 780 Participants |
| Sex: Female, Male Female | 92 Participants | 78 Participants | 170 Participants |
| Sex: Female, Male Male | 380 Participants | 397 Participants | 777 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 388 / 472 | 406 / 475 |
| other Total, other adverse events | 420 / 468 | 429 / 441 |
| serious Total, serious adverse events | 313 / 468 | 290 / 441 |
Outcome results
Primary
Overall Survival (OS) in All Randomized Participants
Overall survival (OS) is defined as the time between randomization and death. For participants without documentation of death, OS will be censored on the last date the participant was known to be alive. Overall survival will be censored at the date of randomization for participants who were randomized but had no follow-up. Survival follow-up will be conducted every 3 months after participants off-treatment date. (Based on Kaplan-Meier estimates)
Time frame: From randomization to date of death or date the participant was last known to be alive (Up to approximately 55 months)
Population: All randomized participants
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Nivolumab + Ipilimumab | Overall Survival (OS) in All Randomized Participants | 13.90 Months |
| EXTREME Regimen | Overall Survival (OS) in All Randomized Participants | 13.50 Months |
p-value: 0.495197.9% CI: [0.8, 1.13]Log Rank
Primary
Overall Survival (OS) in Participants With Programmed Death-Ligand 1 (PD-L1) With a Combined Positive Score (CPS) ≥20
Overall survival (OS) is defined as the time between randomization and death. For participants without documentation of death, OS will be censored on the last date the participant was known to be alive. Overall survival will be censored at the date of randomization for participants who were randomized but had no follow-up. Survival follow-up will be conducted every 3 months after participants off-treatment date. (Based on Kaplan-Meier estimates)
Time frame: From randomization to date of death or date the participant was last known to be alive (Up to approximately 55 months)
Population: All randomized PD-L1 CPS \>= 20 participants
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Nivolumab + Ipilimumab | Overall Survival (OS) in Participants With Programmed Death-Ligand 1 (PD-L1) With a Combined Positive Score (CPS) ≥20 | 17.58 Months |
| EXTREME Regimen | Overall Survival (OS) in Participants With Programmed Death-Ligand 1 (PD-L1) With a Combined Positive Score (CPS) ≥20 | 14.59 Months |
p-value: 0.046997.51% CI: [0.59, 1.03]Log Rank
Secondary
Duration of Objective Response (DOR)
The time between the first documented response (Complete response (CR) or partial response (PR)) and progression or death, per RECIST 1.1 by blinded independent central review (BICR) assessment. (Based on Kaplan-Meier Estimates) Complete Response (CR): Disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to \< 10 mm. Partial Response (PR): At least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters.
Time frame: From randomization to the first documented response (CR or PR) and progression (up to approximately 65 months)
Population: All randomized participants and randomized PD-L1 CPS \>= 20 participants with a BOR response of CR or PR
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Nivolumab + Ipilimumab | Duration of Objective Response (DOR) | All randomized participants | 16.59 Months |
| Nivolumab + Ipilimumab | Duration of Objective Response (DOR) | Randomized PD-L1 CPS >= 20 participants | 33.51 Months |
| EXTREME Regimen | Duration of Objective Response (DOR) | All randomized participants | 5.88 Months |
| EXTREME Regimen | Duration of Objective Response (DOR) | Randomized PD-L1 CPS >= 20 participants | 6.97 Months |
Secondary
Objective Response Rate (ORR)
Objective Response Rate (ORR) is defined as the number of participants with a best overall response (BOR) of complete response (CR) or partial response (PR). Based on Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 criteria by blinded independent central review (BICR) assessment. Complete Response (CR): Disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to \< 10 mm. Partial Response (PR): At least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters.
Time frame: From randomization up to approximately 65 months
Population: All randomized participants and randomized PD-L1 CPS \>= 20 participants
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Nivolumab + Ipilimumab | Objective Response Rate (ORR) | All randomized participants | 24.2 Percent |
| Nivolumab + Ipilimumab | Objective Response Rate (ORR) | Randomized PD-L1 CPS >= 20 participants | 34.1 Percent |
| EXTREME Regimen | Objective Response Rate (ORR) | All randomized participants | 37.1 Percent |
| EXTREME Regimen | Objective Response Rate (ORR) | Randomized PD-L1 CPS >= 20 participants | 35.4 Percent |
Secondary
Overall Survival (OS) in Randomized Participants With Programmed Death-Ligand 1 (PD-L1) With a Combined Positive Score (CPS) ≥ 1
Overall survival (OS) is defined as the time between randomization and death. For participants without documentation of death, OS will be censored on the last date the participant was known to be alive. Overall survival will be censored at the date of randomization for participants who were randomized but had no follow-up. Survival follow-up will be conducted every 3 months after participants off-treatment date. (Based on Kaplan-Meier estimates)
Time frame: From randomization to date of death or date the participant was last known to be alive (Up to approximately 65 months)
Population: All randomized PD-L1 CPS ≥ 1 participants
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Nivolumab + Ipilimumab | Overall Survival (OS) in Randomized Participants With Programmed Death-Ligand 1 (PD-L1) With a Combined Positive Score (CPS) ≥ 1 | 15.67 Months |
| EXTREME Regimen | Overall Survival (OS) in Randomized Participants With Programmed Death-Ligand 1 (PD-L1) With a Combined Positive Score (CPS) ≥ 1 | 13.24 Months |
95% CI: [0.68, 0.95]
Secondary
Progression Free Survival (PFS)
PFS is defined as the time between the date of randomization and the date of first documented tumor progression, based on Blinded Independent Central Review (BICR) assessments (per Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 criteria), or death due to any cause, whichever occurs first. Participants who neither progress nor die will be censored on the date of their last tumor assessment. Participants who receive subsequent anti-cancer therapy prior to documented progression, will be censored on the date of their last tumor assessment prior to subsequent therapy. (Based on Kaplan-Meier Estimates) Progression is defined as at least a 20% increase in the sum of diameters of target lesions, in addition the sum must also demonstrate an absolute increase of at least 5 mm. (Note: the appearance of one or more new lesions is also considered progression).
Time frame: From randomization to disease progression or death (Up to approximately 65 months)
Population: All randomized participants and randomized PD-L1 CPS \>= 20 participants
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Nivolumab + Ipilimumab | Progression Free Survival (PFS) | Randomized participants | 3.29 Months |
| Nivolumab + Ipilimumab | Progression Free Survival (PFS) | Randomized PD-L1 CPS >= 20 participants | 5.39 Months |
| EXTREME Regimen | Progression Free Survival (PFS) | Randomized participants | 6.77 Months |
| EXTREME Regimen | Progression Free Survival (PFS) | Randomized PD-L1 CPS >= 20 participants | 6.97 Months |
95% CI: [1.19, 1.63]
95% CI: [0.77, 1.3]
Post Hoc
Overall Survival (OS) in All Randomized Participants - Extended Collection
Overall survival (OS) is defined as the time between randomization and death. For participants without documentation of death, OS will be censored on the last date the participant was known to be alive. Overall survival will be censored at the date of randomization for participants who were randomized but had no follow-up. Survival follow-up will be conducted every 3 months after participants off-treatment date. (Based on Kaplan-Meier estimates)
Time frame: From randomization to date of death or date the participant was last known to be alive (Up to approximately 65 months)
Population: All randomized participants
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Nivolumab + Ipilimumab | Overall Survival (OS) in All Randomized Participants - Extended Collection | 13.90 Months |
| EXTREME Regimen | Overall Survival (OS) in All Randomized Participants - Extended Collection | 13.50 Months |
95% CI: [0.82, 1.08]
Post Hoc
Overall Survival (OS) in Participants With Programmed Death-Ligand 1 (PD-L1) With a Combined Positive Score (CPS) ≥20 - Extended Collection
Overall survival (OS) is defined as the time between randomization and death. For participants without documentation of death, OS will be censored on the last date the participant was known to be alive. Overall survival will be censored at the date of randomization for participants who were randomized but had no follow-up. Survival follow-up will be conducted every 3 months after participants off-treatment date. (Based on Kaplan-Meier estimates)
Time frame: From randomization to date of death or date the participant was last known to be alive (Up to approximately 65 months)
Population: All randomized PD-L1 CPS \>= 20 participants
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Nivolumab + Ipilimumab | Overall Survival (OS) in Participants With Programmed Death-Ligand 1 (PD-L1) With a Combined Positive Score (CPS) ≥20 - Extended Collection | 17.74 Months |
| EXTREME Regimen | Overall Survival (OS) in Participants With Programmed Death-Ligand 1 (PD-L1) With a Combined Positive Score (CPS) ≥20 - Extended Collection | 14.59 Months |
95% CI: [0.6, 0.97]