Trial Outcomes & Findings for Study to Assess the Efficacy and Safety of Nivolumab in Combination With Paclitaxel in Subjects With Head and Neck Cancer Unable for Cisplatin-based Chemotherapy (NIVOTAX) (NCT NCT04282109)

Last Updated: 2025-06-26

Results Overview

OS is defined as the time between the date of randomization and the date of death. For subjects without documentation of death, OS will be censored on the last date the subject was known to be alive.

Recruitment status

COMPLETED

Study phase

PHASE2

Target enrollment

141 participants

Primary outcome timeframe

2 years

Results posted on

2025-06-26

Participant Flow

Participant milestones

Participant milestones
Measure	Arm 1 NIVOTAX (nivolumab + paclitaxel, follow by maintenance with nivolumab) Nivolumab + Paclitaxel: Combination treatment: Nivolumab 240 mg will be administered via IV infusion every 2 weeks. Paclitaxel 80mg/m2 will be administered via IV infusion weekly. After 12 weeks from the start of the combined treatment paclitaxel will be stopped. Maintenance treatment with nivolumab 480 mg every 4 weeks will start two weeks after the last administration of nivolumab 240 mg. Once nivolumab is administered at 480 mg, paclitaxel can no longer be administered. Nivolumab will be continued alone until disease progression, unacceptable toxicity or withdrawal of consent up to a maximum of 24 months.	Arm 2 ERBITAX (cetuximab + paclitaxel, follow by maintenance with cetuximab) Cetuximab + Paclitaxel: Combination treatment: Cetuximab 250 mg/m2 (first dose of 400 mg/m2) administered via IV infusion weekly plus weekly paclitaxel (80 mg/m2) administered via IV infusion. After 12 weeks from the start of the combined treatment paclitaxel will be stopped and weekly cetuximab will be continued alone until disease progression, unacceptable toxicity or withdrawal of consent up to a maximum of 24 months.
Overall Study STARTED	93	48
Overall Study COMPLETED	93	48
Overall Study NOT COMPLETED	0	0

Reasons for withdrawal

Withdrawal data not reported

Baseline Characteristics

Study to Assess the Efficacy and Safety of Nivolumab in Combination With Paclitaxel in Subjects With Head and Neck Cancer Unable for Cisplatin-based Chemotherapy (NIVOTAX)

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Arm 1 n=93 Participants NIVOTAX (nivolumab + paclitaxel, follow by maintenance with nivolumab). Nivolumab + Paclitaxel: Combination treatment: Nivolumab 240 mg will be administered via IV infusion every 2 weeks. Paclitaxel 80mg/m2 will be administered via IV infusion weekly. After 12 weeks from the start of the combined treatment paclitaxel will be stopped. Maintenance treatment with nivolumab 480 mg every 4 weeks will start two weeks after the last administration of nivolumab 240 mg. Once nivolumab is administered at 480 mg, paclitaxel can no longer be administered. Nivolumab will be continued alone until disease progression, unacceptable toxicity or withdrawal of consent up to a maximum of 24 months.	Arm 2 n=48 Participants ERBITAX (cetuximab + paclitaxel, follow by maintenance with cetuximab). Cetuximab + Paclitaxel: Combination treatment: Cetuximab 250 mg/m2 (first dose of 400 mg/m2) administered via IV infusion weekly plus weekly paclitaxel (80 mg/m2) administered via IV infusion. After 12 weeks from the start of the combined treatment paclitaxel will be stopped and weekly cetuximab will be continued alone until disease progression, unacceptable toxicity or withdrawal of consent up to a maximum of 24 months.	Total n=141 Participants Total of all reporting groups
PD-L1 CPS <1	20 Participants n=99 Participants	11 Participants n=107 Participants	31 Participants n=206 Participants
Age, Categorical <=18 years	0 Participants n=99 Participants	0 Participants n=107 Participants	0 Participants n=206 Participants
Age, Categorical Between 18 and 65 years	42 Participants n=99 Participants	27 Participants n=107 Participants	69 Participants n=206 Participants
Age, Categorical >=65 years	51 Participants n=99 Participants	21 Participants n=107 Participants	72 Participants n=206 Participants
Age, Continuous	66.8 years n=99 Participants	64 years n=107 Participants	65.9 years n=206 Participants
Sex: Female, Male Female	20 Participants n=99 Participants	12 Participants n=107 Participants	32 Participants n=206 Participants
Sex: Female, Male Male	73 Participants n=99 Participants	36 Participants n=107 Participants	109 Participants n=206 Participants
Race/Ethnicity, Customized White/Caucasian	93 Participants n=99 Participants	47 Participants n=107 Participants	140 Participants n=206 Participants
Race/Ethnicity, Customized Arab	0 Participants n=99 Participants	1 Participants n=107 Participants	1 Participants n=206 Participants
Smoking habits: Has the patient ever smoked? Yes	75 Participants n=99 Participants	11 Participants n=107 Participants	86 Participants n=206 Participants
Smoking habits: Has the patient ever smoked? No	18 Participants n=99 Participants	37 Participants n=107 Participants	55 Participants n=206 Participants
Metastatic disease at diagnosis Yes	8 Participants n=99 Participants	3 Participants n=107 Participants	11 Participants n=206 Participants
Metastatic disease at diagnosis No	85 Participants n=99 Participants	45 Participants n=107 Participants	130 Participants n=206 Participants
Karnofsky performance status 70%	36 Participants n=99 Participants	16 Participants n=107 Participants	52 Participants n=206 Participants
Karnofsky performance status 80-100%	57 Participants n=99 Participants	32 Participants n=107 Participants	89 Participants n=206 Participants
PD-L1 CPS ≥1	73 Participants n=99 Participants	37 Participants n=107 Participants	110 Participants n=206 Participants
Type of disease Loco-regional disease	40 Participants n=99 Participants	27 Participants n=107 Participants	67 Participants n=206 Participants
Type of disease Loco-regional disease + M1	26 Participants n=99 Participants	12 Participants n=107 Participants	38 Participants n=206 Participants
Type of disease Metastatic disease	27 Participants n=99 Participants	9 Participants n=107 Participants	36 Participants n=206 Participants
Unable platinum Platinum-refractory	25 Participants n=99 Participants	13 Participants n=107 Participants	38 Participants n=206 Participants
Unable platinum Cumulative cisplatin dose ≥ 225 mg/m²	15 Participants n=99 Participants	8 Participants n=107 Participants	23 Participants n=206 Participants
Unable platinum Platinum sensitive but unable	53 Participants n=99 Participants	27 Participants n=107 Participants	80 Participants n=206 Participants
Smoking habits: Does the patient currently smoke? Yes	21 Participants n=99 Participants	9 Participants n=107 Participants	30 Participants n=206 Participants
Smoking habits: Does the patient currently smoke? No	72 Participants n=99 Participants	39 Participants n=107 Participants	111 Participants n=206 Participants
Alcohol consumption No	31 Participants n=99 Participants	20 Participants n=107 Participants	51 Participants n=206 Participants
Alcohol consumption Current	14 Participants n=99 Participants	12 Participants n=107 Participants	26 Participants n=206 Participants
Alcohol consumption Former	41 Participants n=99 Participants	15 Participants n=107 Participants	56 Participants n=206 Participants
Alcohol consumption Unknown	7 Participants n=99 Participants	1 Participants n=107 Participants	8 Participants n=206 Participants
Primary tumor location Oral cavity	32 Participants n=99 Participants	18 Participants n=107 Participants	50 Participants n=206 Participants
Primary tumor location Oropharynx	33 Participants n=99 Participants	14 Participants n=107 Participants	47 Participants n=206 Participants
Primary tumor location Larynx	17 Participants n=99 Participants	5 Participants n=107 Participants	22 Participants n=206 Participants
Primary tumor location Hypopharynx	11 Participants n=99 Participants	11 Participants n=107 Participants	22 Participants n=206 Participants

PRIMARY outcome

Timeframe: 2 years

OS is defined as the time between the date of randomization and the date of death. For subjects without documentation of death, OS will be censored on the last date the subject was known to be alive.

Outcome measures

Outcome measures
Measure	Arm 1 n=93 Participants NIVOTAX (nivolumab + paclitaxel, follow by maintenance with nivolumab) Nivolumab + Paclitaxel: Combination treatment: Nivolumab 240 mg will be administered via IV infusion every 2 weeks. Paclitaxel 80mg/m2 will be administered via IV infusion weekly. After 12 weeks from the start of the combined treatment paclitaxel will be stopped. Maintenance treatment with nivolumab 480 mg every 4 weeks will start two weeks after the last administration of nivolumab 240 mg. Once nivolumab is administered at 480 mg, paclitaxel can no longer be administered. Nivolumab will be continued alone until disease progression, unacceptable toxicity or withdrawal of consent up to a maximum of 24 months.	Arm 2 n=48 Participants ERBITAX (cetuximab + paclitaxel, follow by maintenance with cetuximab) Cetuximab + Paclitaxel: Combination treatment: Cetuximab 250 mg/m2 (first dose of 400 mg/m2) administered via IV infusion weekly plus weekly paclitaxel (80 mg/m2) administered via IV infusion. After 12 weeks from the start of the combined treatment paclitaxel will be stopped and weekly cetuximab will be continued alone until disease progression, unacceptable toxicity or withdrawal of consent up to a maximum of 24 months.	Arm 2 - CPS <1 ERBITAX - CPS \<1	Arm 2 - CPS >=1 ERBITAX - CPS \>=1	Arm 2 - Group 2 ERBITAX - Group 2 Platinum sensitive but unable for cisplatin based therapy according to one of these criteria: 1. Karnofsky grade 70% or 2. Impaired renal function, creatinine clearance \>30 mL/min and \<80 mL/min GFR could be assessed by direct measurement (EDTA or creatinine clearance) if available or by calculation from serum or plasma creatinine, or 3. Class III heart failure according to the New York Heart Association, or 4. Grade ≥2 hearing loss, according to the NCI CTCAE v 5.0, or 5. History of allergic reactions to cisplatin, carboplatin, or other platinum-containing compounds.	Arm 2 - Group 3 ERBITAX - Group 3 Platinum sensitive but prior dose of cisplatin ≥225 mg/m² for locally advanced disease (one third of the patients - 47 patients) (a patient who received prior RT + 3 cycles of cisplatin 100 mg/m2 or 3 cycles induction TPF (with cisplatin ≥75/m2) for locally advanced primary HN cancer). The interval from the last cycle of cisplatin and the start of first line treatment for R/M disease is \>6 months.
Two Years Overall Survival (OS)	24.7 percentage of participants Interval 15.9 to 33.5	13.4 percentage of participants Interval 3.6 to 23.2	—	—	—	—

SECONDARY outcome

Timeframe: Up to 45 months

PFS is defined as the time from randomization to the date of first documented disease progression, as assessed by the investigator using RECIST 1.1 criteria, or death due to any cause, whichever occurs first.

Outcome measures

Outcome measures
Measure	Arm 1 n=93 Participants NIVOTAX (nivolumab + paclitaxel, follow by maintenance with nivolumab) Nivolumab + Paclitaxel: Combination treatment: Nivolumab 240 mg will be administered via IV infusion every 2 weeks. Paclitaxel 80mg/m2 will be administered via IV infusion weekly. After 12 weeks from the start of the combined treatment paclitaxel will be stopped. Maintenance treatment with nivolumab 480 mg every 4 weeks will start two weeks after the last administration of nivolumab 240 mg. Once nivolumab is administered at 480 mg, paclitaxel can no longer be administered. Nivolumab will be continued alone until disease progression, unacceptable toxicity or withdrawal of consent up to a maximum of 24 months.	Arm 2 n=48 Participants ERBITAX (cetuximab + paclitaxel, follow by maintenance with cetuximab) Cetuximab + Paclitaxel: Combination treatment: Cetuximab 250 mg/m2 (first dose of 400 mg/m2) administered via IV infusion weekly plus weekly paclitaxel (80 mg/m2) administered via IV infusion. After 12 weeks from the start of the combined treatment paclitaxel will be stopped and weekly cetuximab will be continued alone until disease progression, unacceptable toxicity or withdrawal of consent up to a maximum of 24 months.	Arm 2 - CPS <1 ERBITAX - CPS \<1	Arm 2 - CPS >=1 ERBITAX - CPS \>=1	Arm 2 - Group 2 ERBITAX - Group 2 Platinum sensitive but unable for cisplatin based therapy according to one of these criteria: 1. Karnofsky grade 70% or 2. Impaired renal function, creatinine clearance \>30 mL/min and \<80 mL/min GFR could be assessed by direct measurement (EDTA or creatinine clearance) if available or by calculation from serum or plasma creatinine, or 3. Class III heart failure according to the New York Heart Association, or 4. Grade ≥2 hearing loss, according to the NCI CTCAE v 5.0, or 5. History of allergic reactions to cisplatin, carboplatin, or other platinum-containing compounds.	Arm 2 - Group 3 ERBITAX - Group 3 Platinum sensitive but prior dose of cisplatin ≥225 mg/m² for locally advanced disease (one third of the patients - 47 patients) (a patient who received prior RT + 3 cycles of cisplatin 100 mg/m2 or 3 cycles induction TPF (with cisplatin ≥75/m2) for locally advanced primary HN cancer). The interval from the last cycle of cisplatin and the start of first line treatment for R/M disease is \>6 months.
Progression Free Survival (PFS)	5.6 months Interval 3.5 to 7.6	5.3 months Interval 2.7 to 7.9	—	—	—	—

SECONDARY outcome

Timeframe: Up to 2 years

ORR is defined as the number of subjects with a best overall response (BOR) of a complete response (CR) or partial response (PR) divided by the number of randomized subjects for each treatment group.

Outcome measures

Outcome measures
Measure	Arm 1 n=93 Participants NIVOTAX (nivolumab + paclitaxel, follow by maintenance with nivolumab) Nivolumab + Paclitaxel: Combination treatment: Nivolumab 240 mg will be administered via IV infusion every 2 weeks. Paclitaxel 80mg/m2 will be administered via IV infusion weekly. After 12 weeks from the start of the combined treatment paclitaxel will be stopped. Maintenance treatment with nivolumab 480 mg every 4 weeks will start two weeks after the last administration of nivolumab 240 mg. Once nivolumab is administered at 480 mg, paclitaxel can no longer be administered. Nivolumab will be continued alone until disease progression, unacceptable toxicity or withdrawal of consent up to a maximum of 24 months.	Arm 2 n=48 Participants ERBITAX (cetuximab + paclitaxel, follow by maintenance with cetuximab) Cetuximab + Paclitaxel: Combination treatment: Cetuximab 250 mg/m2 (first dose of 400 mg/m2) administered via IV infusion weekly plus weekly paclitaxel (80 mg/m2) administered via IV infusion. After 12 weeks from the start of the combined treatment paclitaxel will be stopped and weekly cetuximab will be continued alone until disease progression, unacceptable toxicity or withdrawal of consent up to a maximum of 24 months.	Arm 2 - CPS <1 ERBITAX - CPS \<1	Arm 2 - CPS >=1 ERBITAX - CPS \>=1	Arm 2 - Group 2 ERBITAX - Group 2 Platinum sensitive but unable for cisplatin based therapy according to one of these criteria: 1. Karnofsky grade 70% or 2. Impaired renal function, creatinine clearance \>30 mL/min and \<80 mL/min GFR could be assessed by direct measurement (EDTA or creatinine clearance) if available or by calculation from serum or plasma creatinine, or 3. Class III heart failure according to the New York Heart Association, or 4. Grade ≥2 hearing loss, according to the NCI CTCAE v 5.0, or 5. History of allergic reactions to cisplatin, carboplatin, or other platinum-containing compounds.	Arm 2 - Group 3 ERBITAX - Group 3 Platinum sensitive but prior dose of cisplatin ≥225 mg/m² for locally advanced disease (one third of the patients - 47 patients) (a patient who received prior RT + 3 cycles of cisplatin 100 mg/m2 or 3 cycles induction TPF (with cisplatin ≥75/m2) for locally advanced primary HN cancer). The interval from the last cycle of cisplatin and the start of first line treatment for R/M disease is \>6 months.
Overall Response Rate (ORR)	37.6 percentage of participants Interval 27.8 to 47.5	37.5 percentage of participants Interval 23.8 to 51.2	—	—	—	—

SECONDARY outcome

Timeframe: Up to 2 years

Disease control rate (DCR) is defined as the number of subjects with a best overall response (BOR) of a complete response (CR), partial response (PR) or stable disease (SD) divided by the number of randomized subjects for each treatment group.

Outcome measures

Outcome measures
Measure	Arm 1 n=93 Participants NIVOTAX (nivolumab + paclitaxel, follow by maintenance with nivolumab) Nivolumab + Paclitaxel: Combination treatment: Nivolumab 240 mg will be administered via IV infusion every 2 weeks. Paclitaxel 80mg/m2 will be administered via IV infusion weekly. After 12 weeks from the start of the combined treatment paclitaxel will be stopped. Maintenance treatment with nivolumab 480 mg every 4 weeks will start two weeks after the last administration of nivolumab 240 mg. Once nivolumab is administered at 480 mg, paclitaxel can no longer be administered. Nivolumab will be continued alone until disease progression, unacceptable toxicity or withdrawal of consent up to a maximum of 24 months.	Arm 2 n=48 Participants ERBITAX (cetuximab + paclitaxel, follow by maintenance with cetuximab) Cetuximab + Paclitaxel: Combination treatment: Cetuximab 250 mg/m2 (first dose of 400 mg/m2) administered via IV infusion weekly plus weekly paclitaxel (80 mg/m2) administered via IV infusion. After 12 weeks from the start of the combined treatment paclitaxel will be stopped and weekly cetuximab will be continued alone until disease progression, unacceptable toxicity or withdrawal of consent up to a maximum of 24 months.	Arm 2 - CPS <1 ERBITAX - CPS \<1	Arm 2 - CPS >=1 ERBITAX - CPS \>=1	Arm 2 - Group 2 ERBITAX - Group 2 Platinum sensitive but unable for cisplatin based therapy according to one of these criteria: 1. Karnofsky grade 70% or 2. Impaired renal function, creatinine clearance \>30 mL/min and \<80 mL/min GFR could be assessed by direct measurement (EDTA or creatinine clearance) if available or by calculation from serum or plasma creatinine, or 3. Class III heart failure according to the New York Heart Association, or 4. Grade ≥2 hearing loss, according to the NCI CTCAE v 5.0, or 5. History of allergic reactions to cisplatin, carboplatin, or other platinum-containing compounds.	Arm 2 - Group 3 ERBITAX - Group 3 Platinum sensitive but prior dose of cisplatin ≥225 mg/m² for locally advanced disease (one third of the patients - 47 patients) (a patient who received prior RT + 3 cycles of cisplatin 100 mg/m2 or 3 cycles induction TPF (with cisplatin ≥75/m2) for locally advanced primary HN cancer). The interval from the last cycle of cisplatin and the start of first line treatment for R/M disease is \>6 months.
Disease Control Rate (DCR)	74.2 percentage of participants Interval 65.3 to 83.1	79.2 percentage of participants Interval 67.7 to 90.7	—	—	—	—

SECONDARY outcome

Timeframe: Up to 45 months

Duration of Response (DoR) is defined as the time between the date of first confirmed response to the date of the first documented tumor progression (per RECIST 1.1), or death due to any cause, whichever occurs first.

Outcome measures

Outcome measures
Measure	Arm 1 n=35 Participants NIVOTAX (nivolumab + paclitaxel, follow by maintenance with nivolumab) Nivolumab + Paclitaxel: Combination treatment: Nivolumab 240 mg will be administered via IV infusion every 2 weeks. Paclitaxel 80mg/m2 will be administered via IV infusion weekly. After 12 weeks from the start of the combined treatment paclitaxel will be stopped. Maintenance treatment with nivolumab 480 mg every 4 weeks will start two weeks after the last administration of nivolumab 240 mg. Once nivolumab is administered at 480 mg, paclitaxel can no longer be administered. Nivolumab will be continued alone until disease progression, unacceptable toxicity or withdrawal of consent up to a maximum of 24 months.	Arm 2 n=18 Participants ERBITAX (cetuximab + paclitaxel, follow by maintenance with cetuximab) Cetuximab + Paclitaxel: Combination treatment: Cetuximab 250 mg/m2 (first dose of 400 mg/m2) administered via IV infusion weekly plus weekly paclitaxel (80 mg/m2) administered via IV infusion. After 12 weeks from the start of the combined treatment paclitaxel will be stopped and weekly cetuximab will be continued alone until disease progression, unacceptable toxicity or withdrawal of consent up to a maximum of 24 months.	Arm 2 - CPS <1 ERBITAX - CPS \<1	Arm 2 - CPS >=1 ERBITAX - CPS \>=1	Arm 2 - Group 2 ERBITAX - Group 2 Platinum sensitive but unable for cisplatin based therapy according to one of these criteria: 1. Karnofsky grade 70% or 2. Impaired renal function, creatinine clearance \>30 mL/min and \<80 mL/min GFR could be assessed by direct measurement (EDTA or creatinine clearance) if available or by calculation from serum or plasma creatinine, or 3. Class III heart failure according to the New York Heart Association, or 4. Grade ≥2 hearing loss, according to the NCI CTCAE v 5.0, or 5. History of allergic reactions to cisplatin, carboplatin, or other platinum-containing compounds.	Arm 2 - Group 3 ERBITAX - Group 3 Platinum sensitive but prior dose of cisplatin ≥225 mg/m² for locally advanced disease (one third of the patients - 47 patients) (a patient who received prior RT + 3 cycles of cisplatin 100 mg/m2 or 3 cycles induction TPF (with cisplatin ≥75/m2) for locally advanced primary HN cancer). The interval from the last cycle of cisplatin and the start of first line treatment for R/M disease is \>6 months.
Duration of Response (DoR)	9 month Interval 7.6 to 10.5	7.6 month Interval 4.9 to 10.4	—	—	—	—

SECONDARY outcome

Timeframe: 6 months

Probability of progression at 6 months.

Outcome measures

Outcome measures
Measure	Arm 1 n=93 Participants NIVOTAX (nivolumab + paclitaxel, follow by maintenance with nivolumab) Nivolumab + Paclitaxel: Combination treatment: Nivolumab 240 mg will be administered via IV infusion every 2 weeks. Paclitaxel 80mg/m2 will be administered via IV infusion weekly. After 12 weeks from the start of the combined treatment paclitaxel will be stopped. Maintenance treatment with nivolumab 480 mg every 4 weeks will start two weeks after the last administration of nivolumab 240 mg. Once nivolumab is administered at 480 mg, paclitaxel can no longer be administered. Nivolumab will be continued alone until disease progression, unacceptable toxicity or withdrawal of consent up to a maximum of 24 months.	Arm 2 n=48 Participants ERBITAX (cetuximab + paclitaxel, follow by maintenance with cetuximab) Cetuximab + Paclitaxel: Combination treatment: Cetuximab 250 mg/m2 (first dose of 400 mg/m2) administered via IV infusion weekly plus weekly paclitaxel (80 mg/m2) administered via IV infusion. After 12 weeks from the start of the combined treatment paclitaxel will be stopped and weekly cetuximab will be continued alone until disease progression, unacceptable toxicity or withdrawal of consent up to a maximum of 24 months.	Arm 2 - CPS <1 ERBITAX - CPS \<1	Arm 2 - CPS >=1 ERBITAX - CPS \>=1	Arm 2 - Group 2 ERBITAX - Group 2 Platinum sensitive but unable for cisplatin based therapy according to one of these criteria: 1. Karnofsky grade 70% or 2. Impaired renal function, creatinine clearance \>30 mL/min and \<80 mL/min GFR could be assessed by direct measurement (EDTA or creatinine clearance) if available or by calculation from serum or plasma creatinine, or 3. Class III heart failure according to the New York Heart Association, or 4. Grade ≥2 hearing loss, according to the NCI CTCAE v 5.0, or 5. History of allergic reactions to cisplatin, carboplatin, or other platinum-containing compounds.	Arm 2 - Group 3 ERBITAX - Group 3 Platinum sensitive but prior dose of cisplatin ≥225 mg/m² for locally advanced disease (one third of the patients - 47 patients) (a patient who received prior RT + 3 cycles of cisplatin 100 mg/m2 or 3 cycles induction TPF (with cisplatin ≥75/m2) for locally advanced primary HN cancer). The interval from the last cycle of cisplatin and the start of first line treatment for R/M disease is \>6 months.
6-months Progression-free Survival Rate	47.5 percentage of participants Interval 37.3 to 57.7	50.0 percentage of participants Interval 35.9 to 64.1	—	—	—	—

SECONDARY outcome

Timeframe: Up to 45 months

OS is defined as the time between the date of randomization and the date of death.

Outcome measures

Outcome measures
Measure	Arm 1 n=37 Participants NIVOTAX (nivolumab + paclitaxel, follow by maintenance with nivolumab) Nivolumab + Paclitaxel: Combination treatment: Nivolumab 240 mg will be administered via IV infusion every 2 weeks. Paclitaxel 80mg/m2 will be administered via IV infusion weekly. After 12 weeks from the start of the combined treatment paclitaxel will be stopped. Maintenance treatment with nivolumab 480 mg every 4 weeks will start two weeks after the last administration of nivolumab 240 mg. Once nivolumab is administered at 480 mg, paclitaxel can no longer be administered. Nivolumab will be continued alone until disease progression, unacceptable toxicity or withdrawal of consent up to a maximum of 24 months.	Arm 2 n=13 Participants ERBITAX (cetuximab + paclitaxel, follow by maintenance with cetuximab) Cetuximab + Paclitaxel: Combination treatment: Cetuximab 250 mg/m2 (first dose of 400 mg/m2) administered via IV infusion weekly plus weekly paclitaxel (80 mg/m2) administered via IV infusion. After 12 weeks from the start of the combined treatment paclitaxel will be stopped and weekly cetuximab will be continued alone until disease progression, unacceptable toxicity or withdrawal of consent up to a maximum of 24 months.	Arm 2 - CPS <1 ERBITAX - CPS \<1	Arm 2 - CPS >=1 ERBITAX - CPS \>=1	Arm 2 - Group 2 ERBITAX - Group 2 Platinum sensitive but unable for cisplatin based therapy according to one of these criteria: 1. Karnofsky grade 70% or 2. Impaired renal function, creatinine clearance \>30 mL/min and \<80 mL/min GFR could be assessed by direct measurement (EDTA or creatinine clearance) if available or by calculation from serum or plasma creatinine, or 3. Class III heart failure according to the New York Heart Association, or 4. Grade ≥2 hearing loss, according to the NCI CTCAE v 5.0, or 5. History of allergic reactions to cisplatin, carboplatin, or other platinum-containing compounds.	Arm 2 - Group 3 ERBITAX - Group 3 Platinum sensitive but prior dose of cisplatin ≥225 mg/m² for locally advanced disease (one third of the patients - 47 patients) (a patient who received prior RT + 3 cycles of cisplatin 100 mg/m2 or 3 cycles induction TPF (with cisplatin ≥75/m2) for locally advanced primary HN cancer). The interval from the last cycle of cisplatin and the start of first line treatment for R/M disease is \>6 months.
Overall Survival in Patients ≥ 70 Years.	13.03 months Interval 3.9 to 22.2	14.54 months Interval 7.99 to 21.01	—	—	—	—

SECONDARY outcome

Timeframe: Up to 45 months

Outcome measures

Outcome measures
Measure	Arm 1 n=37 Participants NIVOTAX (nivolumab + paclitaxel, follow by maintenance with nivolumab) Nivolumab + Paclitaxel: Combination treatment: Nivolumab 240 mg will be administered via IV infusion every 2 weeks. Paclitaxel 80mg/m2 will be administered via IV infusion weekly. After 12 weeks from the start of the combined treatment paclitaxel will be stopped. Maintenance treatment with nivolumab 480 mg every 4 weeks will start two weeks after the last administration of nivolumab 240 mg. Once nivolumab is administered at 480 mg, paclitaxel can no longer be administered. Nivolumab will be continued alone until disease progression, unacceptable toxicity or withdrawal of consent up to a maximum of 24 months.	Arm 2 n=13 Participants ERBITAX (cetuximab + paclitaxel, follow by maintenance with cetuximab) Cetuximab + Paclitaxel: Combination treatment: Cetuximab 250 mg/m2 (first dose of 400 mg/m2) administered via IV infusion weekly plus weekly paclitaxel (80 mg/m2) administered via IV infusion. After 12 weeks from the start of the combined treatment paclitaxel will be stopped and weekly cetuximab will be continued alone until disease progression, unacceptable toxicity or withdrawal of consent up to a maximum of 24 months.	Arm 2 - CPS <1 ERBITAX - CPS \<1	Arm 2 - CPS >=1 ERBITAX - CPS \>=1	Arm 2 - Group 2 ERBITAX - Group 2 Platinum sensitive but unable for cisplatin based therapy according to one of these criteria: 1. Karnofsky grade 70% or 2. Impaired renal function, creatinine clearance \>30 mL/min and \<80 mL/min GFR could be assessed by direct measurement (EDTA or creatinine clearance) if available or by calculation from serum or plasma creatinine, or 3. Class III heart failure according to the New York Heart Association, or 4. Grade ≥2 hearing loss, according to the NCI CTCAE v 5.0, or 5. History of allergic reactions to cisplatin, carboplatin, or other platinum-containing compounds.	Arm 2 - Group 3 ERBITAX - Group 3 Platinum sensitive but prior dose of cisplatin ≥225 mg/m² for locally advanced disease (one third of the patients - 47 patients) (a patient who received prior RT + 3 cycles of cisplatin 100 mg/m2 or 3 cycles induction TPF (with cisplatin ≥75/m2) for locally advanced primary HN cancer). The interval from the last cycle of cisplatin and the start of first line treatment for R/M disease is \>6 months.
Progression Free Survival in Patients ≥ 70 Years.	6.48 month Interval 2.22 to 10.73	9.97 month Interval 3.59 to 16.34	—	—	—	—

SECONDARY outcome

Timeframe: Up to 2 years

Population: Patients ≥ 70 years.

ORR is defined as the number of subjects with a best overall response (BOR) of a complete response (CR) or partial response (PR) divided by the number of randomized subjects for each treatment group.

Outcome measures

Outcome measures
Measure	Arm 1 n=37 Participants NIVOTAX (nivolumab + paclitaxel, follow by maintenance with nivolumab) Nivolumab + Paclitaxel: Combination treatment: Nivolumab 240 mg will be administered via IV infusion every 2 weeks. Paclitaxel 80mg/m2 will be administered via IV infusion weekly. After 12 weeks from the start of the combined treatment paclitaxel will be stopped. Maintenance treatment with nivolumab 480 mg every 4 weeks will start two weeks after the last administration of nivolumab 240 mg. Once nivolumab is administered at 480 mg, paclitaxel can no longer be administered. Nivolumab will be continued alone until disease progression, unacceptable toxicity or withdrawal of consent up to a maximum of 24 months.	Arm 2 n=13 Participants ERBITAX (cetuximab + paclitaxel, follow by maintenance with cetuximab) Cetuximab + Paclitaxel: Combination treatment: Cetuximab 250 mg/m2 (first dose of 400 mg/m2) administered via IV infusion weekly plus weekly paclitaxel (80 mg/m2) administered via IV infusion. After 12 weeks from the start of the combined treatment paclitaxel will be stopped and weekly cetuximab will be continued alone until disease progression, unacceptable toxicity or withdrawal of consent up to a maximum of 24 months.	Arm 2 - CPS <1 ERBITAX - CPS \<1	Arm 2 - CPS >=1 ERBITAX - CPS \>=1	Arm 2 - Group 2 ERBITAX - Group 2 Platinum sensitive but unable for cisplatin based therapy according to one of these criteria: 1. Karnofsky grade 70% or 2. Impaired renal function, creatinine clearance \>30 mL/min and \<80 mL/min GFR could be assessed by direct measurement (EDTA or creatinine clearance) if available or by calculation from serum or plasma creatinine, or 3. Class III heart failure according to the New York Heart Association, or 4. Grade ≥2 hearing loss, according to the NCI CTCAE v 5.0, or 5. History of allergic reactions to cisplatin, carboplatin, or other platinum-containing compounds.	Arm 2 - Group 3 ERBITAX - Group 3 Platinum sensitive but prior dose of cisplatin ≥225 mg/m² for locally advanced disease (one third of the patients - 47 patients) (a patient who received prior RT + 3 cycles of cisplatin 100 mg/m2 or 3 cycles induction TPF (with cisplatin ≥75/m2) for locally advanced primary HN cancer). The interval from the last cycle of cisplatin and the start of first line treatment for R/M disease is \>6 months.
Overall Response Rate in Patients ≥ 70 Years.	40.5 percentage of participants	53.8 percentage of participants	—	—	—	—

SECONDARY outcome

Timeframe: Up to 45 months

OS is defined as the time between the date of randomization and the date of death.

Outcome measures

Outcome measures
Measure	Arm 1 n=20 Participants NIVOTAX (nivolumab + paclitaxel, follow by maintenance with nivolumab) Nivolumab + Paclitaxel: Combination treatment: Nivolumab 240 mg will be administered via IV infusion every 2 weeks. Paclitaxel 80mg/m2 will be administered via IV infusion weekly. After 12 weeks from the start of the combined treatment paclitaxel will be stopped. Maintenance treatment with nivolumab 480 mg every 4 weeks will start two weeks after the last administration of nivolumab 240 mg. Once nivolumab is administered at 480 mg, paclitaxel can no longer be administered. Nivolumab will be continued alone until disease progression, unacceptable toxicity or withdrawal of consent up to a maximum of 24 months.	Arm 2 n=73 Participants ERBITAX (cetuximab + paclitaxel, follow by maintenance with cetuximab) Cetuximab + Paclitaxel: Combination treatment: Cetuximab 250 mg/m2 (first dose of 400 mg/m2) administered via IV infusion weekly plus weekly paclitaxel (80 mg/m2) administered via IV infusion. After 12 weeks from the start of the combined treatment paclitaxel will be stopped and weekly cetuximab will be continued alone until disease progression, unacceptable toxicity or withdrawal of consent up to a maximum of 24 months.	Arm 2 - CPS <1 n=11 Participants ERBITAX - CPS \<1	Arm 2 - CPS >=1 n=37 Participants ERBITAX - CPS \>=1	Arm 2 - Group 2 ERBITAX - Group 2 Platinum sensitive but unable for cisplatin based therapy according to one of these criteria: 1. Karnofsky grade 70% or 2. Impaired renal function, creatinine clearance \>30 mL/min and \<80 mL/min GFR could be assessed by direct measurement (EDTA or creatinine clearance) if available or by calculation from serum or plasma creatinine, or 3. Class III heart failure according to the New York Heart Association, or 4. Grade ≥2 hearing loss, according to the NCI CTCAE v 5.0, or 5. History of allergic reactions to cisplatin, carboplatin, or other platinum-containing compounds.	Arm 2 - Group 3 ERBITAX - Group 3 Platinum sensitive but prior dose of cisplatin ≥225 mg/m² for locally advanced disease (one third of the patients - 47 patients) (a patient who received prior RT + 3 cycles of cisplatin 100 mg/m2 or 3 cycles induction TPF (with cisplatin ≥75/m2) for locally advanced primary HN cancer). The interval from the last cycle of cisplatin and the start of first line treatment for R/M disease is \>6 months.
Overall Survival Based on PDL1 Expression (CPS).	11.94 months Interval 8.55 to 15.33	12.24 months Interval 8.9 to 15.57	14.54 months Interval 7.51 to 21.57	11.18 months Interval 8.99 to 13.38	—	—

SECONDARY outcome

Timeframe: Up to 45 months

Outcome measures

Outcome measures
Measure	Arm 1 n=20 Participants NIVOTAX (nivolumab + paclitaxel, follow by maintenance with nivolumab) Nivolumab + Paclitaxel: Combination treatment: Nivolumab 240 mg will be administered via IV infusion every 2 weeks. Paclitaxel 80mg/m2 will be administered via IV infusion weekly. After 12 weeks from the start of the combined treatment paclitaxel will be stopped. Maintenance treatment with nivolumab 480 mg every 4 weeks will start two weeks after the last administration of nivolumab 240 mg. Once nivolumab is administered at 480 mg, paclitaxel can no longer be administered. Nivolumab will be continued alone until disease progression, unacceptable toxicity or withdrawal of consent up to a maximum of 24 months.	Arm 2 n=73 Participants ERBITAX (cetuximab + paclitaxel, follow by maintenance with cetuximab) Cetuximab + Paclitaxel: Combination treatment: Cetuximab 250 mg/m2 (first dose of 400 mg/m2) administered via IV infusion weekly plus weekly paclitaxel (80 mg/m2) administered via IV infusion. After 12 weeks from the start of the combined treatment paclitaxel will be stopped and weekly cetuximab will be continued alone until disease progression, unacceptable toxicity or withdrawal of consent up to a maximum of 24 months.	Arm 2 - CPS <1 n=11 Participants ERBITAX - CPS \<1	Arm 2 - CPS >=1 n=37 Participants ERBITAX - CPS \>=1	Arm 2 - Group 2 ERBITAX - Group 2 Platinum sensitive but unable for cisplatin based therapy according to one of these criteria: 1. Karnofsky grade 70% or 2. Impaired renal function, creatinine clearance \>30 mL/min and \<80 mL/min GFR could be assessed by direct measurement (EDTA or creatinine clearance) if available or by calculation from serum or plasma creatinine, or 3. Class III heart failure according to the New York Heart Association, or 4. Grade ≥2 hearing loss, according to the NCI CTCAE v 5.0, or 5. History of allergic reactions to cisplatin, carboplatin, or other platinum-containing compounds.	Arm 2 - Group 3 ERBITAX - Group 3 Platinum sensitive but prior dose of cisplatin ≥225 mg/m² for locally advanced disease (one third of the patients - 47 patients) (a patient who received prior RT + 3 cycles of cisplatin 100 mg/m2 or 3 cycles induction TPF (with cisplatin ≥75/m2) for locally advanced primary HN cancer). The interval from the last cycle of cisplatin and the start of first line treatment for R/M disease is \>6 months.
Progression Free Survival Based on PDL1 Expression (CPS).	7.6 months Interval 0.55 to 14.65	5.56 months Interval 4.16 to 6.95	8.72 months Interval 2.65 to 14.79	5.33 months Interval 2.94 to 7.71	—	—

SECONDARY outcome

Timeframe: Up to 2 years

ORR is defined as the number of subjects with a best overall response (BOR) of a complete response (CR) or partial response (PR) divided by the number of randomized subjects for each treatment group.

Outcome measures

Outcome measures
Measure	Arm 1 n=20 Participants NIVOTAX (nivolumab + paclitaxel, follow by maintenance with nivolumab) Nivolumab + Paclitaxel: Combination treatment: Nivolumab 240 mg will be administered via IV infusion every 2 weeks. Paclitaxel 80mg/m2 will be administered via IV infusion weekly. After 12 weeks from the start of the combined treatment paclitaxel will be stopped. Maintenance treatment with nivolumab 480 mg every 4 weeks will start two weeks after the last administration of nivolumab 240 mg. Once nivolumab is administered at 480 mg, paclitaxel can no longer be administered. Nivolumab will be continued alone until disease progression, unacceptable toxicity or withdrawal of consent up to a maximum of 24 months.	Arm 2 n=73 Participants ERBITAX (cetuximab + paclitaxel, follow by maintenance with cetuximab) Cetuximab + Paclitaxel: Combination treatment: Cetuximab 250 mg/m2 (first dose of 400 mg/m2) administered via IV infusion weekly plus weekly paclitaxel (80 mg/m2) administered via IV infusion. After 12 weeks from the start of the combined treatment paclitaxel will be stopped and weekly cetuximab will be continued alone until disease progression, unacceptable toxicity or withdrawal of consent up to a maximum of 24 months.	Arm 2 - CPS <1 n=11 Participants ERBITAX - CPS \<1	Arm 2 - CPS >=1 n=37 Participants ERBITAX - CPS \>=1	Arm 2 - Group 2 ERBITAX - Group 2 Platinum sensitive but unable for cisplatin based therapy according to one of these criteria: 1. Karnofsky grade 70% or 2. Impaired renal function, creatinine clearance \>30 mL/min and \<80 mL/min GFR could be assessed by direct measurement (EDTA or creatinine clearance) if available or by calculation from serum or plasma creatinine, or 3. Class III heart failure according to the New York Heart Association, or 4. Grade ≥2 hearing loss, according to the NCI CTCAE v 5.0, or 5. History of allergic reactions to cisplatin, carboplatin, or other platinum-containing compounds.	Arm 2 - Group 3 ERBITAX - Group 3 Platinum sensitive but prior dose of cisplatin ≥225 mg/m² for locally advanced disease (one third of the patients - 47 patients) (a patient who received prior RT + 3 cycles of cisplatin 100 mg/m2 or 3 cycles induction TPF (with cisplatin ≥75/m2) for locally advanced primary HN cancer). The interval from the last cycle of cisplatin and the start of first line treatment for R/M disease is \>6 months.
Overall Response Rate Based on PDL1 Expression (CPS).	45.0 percentage of participants	35.6 percentage of participants	27.3 percentage of participants	40.5 percentage of participants	—	—

SECONDARY outcome

Timeframe: Up to 45 months

OS is defined as the time between the date of randomization and the date of death.

Outcome measures

Outcome measures
Measure	Arm 1 n=25 Participants NIVOTAX (nivolumab + paclitaxel, follow by maintenance with nivolumab) Nivolumab + Paclitaxel: Combination treatment: Nivolumab 240 mg will be administered via IV infusion every 2 weeks. Paclitaxel 80mg/m2 will be administered via IV infusion weekly. After 12 weeks from the start of the combined treatment paclitaxel will be stopped. Maintenance treatment with nivolumab 480 mg every 4 weeks will start two weeks after the last administration of nivolumab 240 mg. Once nivolumab is administered at 480 mg, paclitaxel can no longer be administered. Nivolumab will be continued alone until disease progression, unacceptable toxicity or withdrawal of consent up to a maximum of 24 months.	Arm 2 n=53 Participants ERBITAX (cetuximab + paclitaxel, follow by maintenance with cetuximab) Cetuximab + Paclitaxel: Combination treatment: Cetuximab 250 mg/m2 (first dose of 400 mg/m2) administered via IV infusion weekly plus weekly paclitaxel (80 mg/m2) administered via IV infusion. After 12 weeks from the start of the combined treatment paclitaxel will be stopped and weekly cetuximab will be continued alone until disease progression, unacceptable toxicity or withdrawal of consent up to a maximum of 24 months.	Arm 2 - CPS <1 n=15 Participants ERBITAX - CPS \<1	Arm 2 - CPS >=1 n=13 Participants ERBITAX - CPS \>=1	Arm 2 - Group 2 n=27 Participants ERBITAX - Group 2 Platinum sensitive but unable for cisplatin based therapy according to one of these criteria: 1. Karnofsky grade 70% or 2. Impaired renal function, creatinine clearance \>30 mL/min and \<80 mL/min GFR could be assessed by direct measurement (EDTA or creatinine clearance) if available or by calculation from serum or plasma creatinine, or 3. Class III heart failure according to the New York Heart Association, or 4. Grade ≥2 hearing loss, according to the NCI CTCAE v 5.0, or 5. History of allergic reactions to cisplatin, carboplatin, or other platinum-containing compounds.	Arm 2 - Group 3 n=8 Participants ERBITAX - Group 3 Platinum sensitive but prior dose of cisplatin ≥225 mg/m² for locally advanced disease (one third of the patients - 47 patients) (a patient who received prior RT + 3 cycles of cisplatin 100 mg/m2 or 3 cycles induction TPF (with cisplatin ≥75/m2) for locally advanced primary HN cancer). The interval from the last cycle of cisplatin and the start of first line treatment for R/M disease is \>6 months.
Overall Survival Based on Cisplatin Ineligibility.	8.95 months Interval 2.08 to 15.82	14.14 months Interval 11.39 to 16.9	10.49 months Interval 6.55 to 14.44	7.5 months Interval 4.83 to 10.16	14.54 months Interval 8.85 to 20.23	12.14 months Interval 7.7 to 16.61

SECONDARY outcome

Timeframe: Up to 45 months

Outcome measures

Outcome measures
Measure	Arm 1 n=25 Participants NIVOTAX (nivolumab + paclitaxel, follow by maintenance with nivolumab) Nivolumab + Paclitaxel: Combination treatment: Nivolumab 240 mg will be administered via IV infusion every 2 weeks. Paclitaxel 80mg/m2 will be administered via IV infusion weekly. After 12 weeks from the start of the combined treatment paclitaxel will be stopped. Maintenance treatment with nivolumab 480 mg every 4 weeks will start two weeks after the last administration of nivolumab 240 mg. Once nivolumab is administered at 480 mg, paclitaxel can no longer be administered. Nivolumab will be continued alone until disease progression, unacceptable toxicity or withdrawal of consent up to a maximum of 24 months.	Arm 2 n=53 Participants ERBITAX (cetuximab + paclitaxel, follow by maintenance with cetuximab) Cetuximab + Paclitaxel: Combination treatment: Cetuximab 250 mg/m2 (first dose of 400 mg/m2) administered via IV infusion weekly plus weekly paclitaxel (80 mg/m2) administered via IV infusion. After 12 weeks from the start of the combined treatment paclitaxel will be stopped and weekly cetuximab will be continued alone until disease progression, unacceptable toxicity or withdrawal of consent up to a maximum of 24 months.	Arm 2 - CPS <1 n=15 Participants ERBITAX - CPS \<1	Arm 2 - CPS >=1 n=13 Participants ERBITAX - CPS \>=1	Arm 2 - Group 2 n=27 Participants ERBITAX - Group 2 Platinum sensitive but unable for cisplatin based therapy according to one of these criteria: 1. Karnofsky grade 70% or 2. Impaired renal function, creatinine clearance \>30 mL/min and \<80 mL/min GFR could be assessed by direct measurement (EDTA or creatinine clearance) if available or by calculation from serum or plasma creatinine, or 3. Class III heart failure according to the New York Heart Association, or 4. Grade ≥2 hearing loss, according to the NCI CTCAE v 5.0, or 5. History of allergic reactions to cisplatin, carboplatin, or other platinum-containing compounds.	Arm 2 - Group 3 n=8 Participants ERBITAX - Group 3 Platinum sensitive but prior dose of cisplatin ≥225 mg/m² for locally advanced disease (one third of the patients - 47 patients) (a patient who received prior RT + 3 cycles of cisplatin 100 mg/m2 or 3 cycles induction TPF (with cisplatin ≥75/m2) for locally advanced primary HN cancer). The interval from the last cycle of cisplatin and the start of first line treatment for R/M disease is \>6 months.
Progression Free Survival Based on Cisplatin Ineligibility.	4.84 months Interval 0.11 to 9.56	5.56 months Interval 3.02 to 8.1	10.23 months Interval 6.63 to 16.83	2.53 months Interval 1.78 to 3.24	7.53 months Interval 6.64 to 8.43	8.26 months Interval 6.8 to 9.71

SECONDARY outcome

Timeframe: Up to 2 years

ORR is defined as the number of subjects with a best overall response (BOR) of a complete response (CR) or partial response (PR) divided by the number of randomized subjects for each treatment group.

Outcome measures

Outcome measures
Measure	Arm 1 n=25 Participants NIVOTAX (nivolumab + paclitaxel, follow by maintenance with nivolumab) Nivolumab + Paclitaxel: Combination treatment: Nivolumab 240 mg will be administered via IV infusion every 2 weeks. Paclitaxel 80mg/m2 will be administered via IV infusion weekly. After 12 weeks from the start of the combined treatment paclitaxel will be stopped. Maintenance treatment with nivolumab 480 mg every 4 weeks will start two weeks after the last administration of nivolumab 240 mg. Once nivolumab is administered at 480 mg, paclitaxel can no longer be administered. Nivolumab will be continued alone until disease progression, unacceptable toxicity or withdrawal of consent up to a maximum of 24 months.	Arm 2 n=53 Participants ERBITAX (cetuximab + paclitaxel, follow by maintenance with cetuximab) Cetuximab + Paclitaxel: Combination treatment: Cetuximab 250 mg/m2 (first dose of 400 mg/m2) administered via IV infusion weekly plus weekly paclitaxel (80 mg/m2) administered via IV infusion. After 12 weeks from the start of the combined treatment paclitaxel will be stopped and weekly cetuximab will be continued alone until disease progression, unacceptable toxicity or withdrawal of consent up to a maximum of 24 months.	Arm 2 - CPS <1 n=15 Participants ERBITAX - CPS \<1	Arm 2 - CPS >=1 n=13 Participants ERBITAX - CPS \>=1	Arm 2 - Group 2 n=27 Participants ERBITAX - Group 2 Platinum sensitive but unable for cisplatin based therapy according to one of these criteria: 1. Karnofsky grade 70% or 2. Impaired renal function, creatinine clearance \>30 mL/min and \<80 mL/min GFR could be assessed by direct measurement (EDTA or creatinine clearance) if available or by calculation from serum or plasma creatinine, or 3. Class III heart failure according to the New York Heart Association, or 4. Grade ≥2 hearing loss, according to the NCI CTCAE v 5.0, or 5. History of allergic reactions to cisplatin, carboplatin, or other platinum-containing compounds.	Arm 2 - Group 3 n=8 Participants ERBITAX - Group 3 Platinum sensitive but prior dose of cisplatin ≥225 mg/m² for locally advanced disease (one third of the patients - 47 patients) (a patient who received prior RT + 3 cycles of cisplatin 100 mg/m2 or 3 cycles induction TPF (with cisplatin ≥75/m2) for locally advanced primary HN cancer). The interval from the last cycle of cisplatin and the start of first line treatment for R/M disease is \>6 months.
Overall Response Rate Based on Cisplatin Ineligibility.	32.0 percentage of participants	39.6 percentage of participants	40.0 percentage of participants	15.4 percentage of participants	51.9 percentage of participants	25.0 percentage of participants

SECONDARY outcome

Timeframe: Up to 45 months

OS is defined as the time between the date of randomization and the date of death.

Outcome measures

Outcome measures
Measure	Arm 1 n=35 Participants NIVOTAX (nivolumab + paclitaxel, follow by maintenance with nivolumab) Nivolumab + Paclitaxel: Combination treatment: Nivolumab 240 mg will be administered via IV infusion every 2 weeks. Paclitaxel 80mg/m2 will be administered via IV infusion weekly. After 12 weeks from the start of the combined treatment paclitaxel will be stopped. Maintenance treatment with nivolumab 480 mg every 4 weeks will start two weeks after the last administration of nivolumab 240 mg. Once nivolumab is administered at 480 mg, paclitaxel can no longer be administered. Nivolumab will be continued alone until disease progression, unacceptable toxicity or withdrawal of consent up to a maximum of 24 months.	Arm 2 n=57 Participants ERBITAX (cetuximab + paclitaxel, follow by maintenance with cetuximab) Cetuximab + Paclitaxel: Combination treatment: Cetuximab 250 mg/m2 (first dose of 400 mg/m2) administered via IV infusion weekly plus weekly paclitaxel (80 mg/m2) administered via IV infusion. After 12 weeks from the start of the combined treatment paclitaxel will be stopped and weekly cetuximab will be continued alone until disease progression, unacceptable toxicity or withdrawal of consent up to a maximum of 24 months.	Arm 2 - CPS <1 n=16 Participants ERBITAX - CPS \<1	Arm 2 - CPS >=1 n=32 Participants ERBITAX - CPS \>=1	Arm 2 - Group 2 ERBITAX - Group 2 Platinum sensitive but unable for cisplatin based therapy according to one of these criteria: 1. Karnofsky grade 70% or 2. Impaired renal function, creatinine clearance \>30 mL/min and \<80 mL/min GFR could be assessed by direct measurement (EDTA or creatinine clearance) if available or by calculation from serum or plasma creatinine, or 3. Class III heart failure according to the New York Heart Association, or 4. Grade ≥2 hearing loss, according to the NCI CTCAE v 5.0, or 5. History of allergic reactions to cisplatin, carboplatin, or other platinum-containing compounds.	Arm 2 - Group 3 ERBITAX - Group 3 Platinum sensitive but prior dose of cisplatin ≥225 mg/m² for locally advanced disease (one third of the patients - 47 patients) (a patient who received prior RT + 3 cycles of cisplatin 100 mg/m2 or 3 cycles induction TPF (with cisplatin ≥75/m2) for locally advanced primary HN cancer). The interval from the last cycle of cisplatin and the start of first line treatment for R/M disease is \>6 months.
Overall Survival Based on Karnofsky.	13.03 months Interval 10.04 to 16.01	11.32 months Interval 6.45 to 16.19	11.18 months Interval 6.48 to 15.89	12.14 months Interval 10.68 to 13.59	—	—

SECONDARY outcome

Timeframe: Up to 45 months

Outcome measures

Outcome measures
Measure	Arm 1 n=35 Participants NIVOTAX (nivolumab + paclitaxel, follow by maintenance with nivolumab) Nivolumab + Paclitaxel: Combination treatment: Nivolumab 240 mg will be administered via IV infusion every 2 weeks. Paclitaxel 80mg/m2 will be administered via IV infusion weekly. After 12 weeks from the start of the combined treatment paclitaxel will be stopped. Maintenance treatment with nivolumab 480 mg every 4 weeks will start two weeks after the last administration of nivolumab 240 mg. Once nivolumab is administered at 480 mg, paclitaxel can no longer be administered. Nivolumab will be continued alone until disease progression, unacceptable toxicity or withdrawal of consent up to a maximum of 24 months.	Arm 2 n=57 Participants ERBITAX (cetuximab + paclitaxel, follow by maintenance with cetuximab) Cetuximab + Paclitaxel: Combination treatment: Cetuximab 250 mg/m2 (first dose of 400 mg/m2) administered via IV infusion weekly plus weekly paclitaxel (80 mg/m2) administered via IV infusion. After 12 weeks from the start of the combined treatment paclitaxel will be stopped and weekly cetuximab will be continued alone until disease progression, unacceptable toxicity or withdrawal of consent up to a maximum of 24 months.	Arm 2 - CPS <1 n=16 Participants ERBITAX - CPS \<1	Arm 2 - CPS >=1 n=32 Participants ERBITAX - CPS \>=1	Arm 2 - Group 2 ERBITAX - Group 2 Platinum sensitive but unable for cisplatin based therapy according to one of these criteria: 1. Karnofsky grade 70% or 2. Impaired renal function, creatinine clearance \>30 mL/min and \<80 mL/min GFR could be assessed by direct measurement (EDTA or creatinine clearance) if available or by calculation from serum or plasma creatinine, or 3. Class III heart failure according to the New York Heart Association, or 4. Grade ≥2 hearing loss, according to the NCI CTCAE v 5.0, or 5. History of allergic reactions to cisplatin, carboplatin, or other platinum-containing compounds.	Arm 2 - Group 3 ERBITAX - Group 3 Platinum sensitive but prior dose of cisplatin ≥225 mg/m² for locally advanced disease (one third of the patients - 47 patients) (a patient who received prior RT + 3 cycles of cisplatin 100 mg/m2 or 3 cycles induction TPF (with cisplatin ≥75/m2) for locally advanced primary HN cancer). The interval from the last cycle of cisplatin and the start of first line treatment for R/M disease is \>6 months.
Progression Free Survival Based on Karnofsky.	6.48 months Interval 3.39 to 9.56	5.56 months Interval 4.2 to 6.92	4.84 months Interval 3.8 to 5.87	7.07 months Interval 3.38 to 10.76	—	—

SECONDARY outcome

Timeframe: Up to 2 years

ORR is defined as the number of subjects with a best overall response (BOR) of a complete response (CR) or partial response (PR) divided by the number of randomized subjects for each treatment group.

Outcome measures

Outcome measures
Measure	Arm 1 n=36 Participants NIVOTAX (nivolumab + paclitaxel, follow by maintenance with nivolumab) Nivolumab + Paclitaxel: Combination treatment: Nivolumab 240 mg will be administered via IV infusion every 2 weeks. Paclitaxel 80mg/m2 will be administered via IV infusion weekly. After 12 weeks from the start of the combined treatment paclitaxel will be stopped. Maintenance treatment with nivolumab 480 mg every 4 weeks will start two weeks after the last administration of nivolumab 240 mg. Once nivolumab is administered at 480 mg, paclitaxel can no longer be administered. Nivolumab will be continued alone until disease progression, unacceptable toxicity or withdrawal of consent up to a maximum of 24 months.	Arm 2 n=57 Participants ERBITAX (cetuximab + paclitaxel, follow by maintenance with cetuximab) Cetuximab + Paclitaxel: Combination treatment: Cetuximab 250 mg/m2 (first dose of 400 mg/m2) administered via IV infusion weekly plus weekly paclitaxel (80 mg/m2) administered via IV infusion. After 12 weeks from the start of the combined treatment paclitaxel will be stopped and weekly cetuximab will be continued alone until disease progression, unacceptable toxicity or withdrawal of consent up to a maximum of 24 months.	Arm 2 - CPS <1 n=16 Participants ERBITAX - CPS \<1	Arm 2 - CPS >=1 n=32 Participants ERBITAX - CPS \>=1	Arm 2 - Group 2 ERBITAX - Group 2 Platinum sensitive but unable for cisplatin based therapy according to one of these criteria: 1. Karnofsky grade 70% or 2. Impaired renal function, creatinine clearance \>30 mL/min and \<80 mL/min GFR could be assessed by direct measurement (EDTA or creatinine clearance) if available or by calculation from serum or plasma creatinine, or 3. Class III heart failure according to the New York Heart Association, or 4. Grade ≥2 hearing loss, according to the NCI CTCAE v 5.0, or 5. History of allergic reactions to cisplatin, carboplatin, or other platinum-containing compounds.	Arm 2 - Group 3 ERBITAX - Group 3 Platinum sensitive but prior dose of cisplatin ≥225 mg/m² for locally advanced disease (one third of the patients - 47 patients) (a patient who received prior RT + 3 cycles of cisplatin 100 mg/m2 or 3 cycles induction TPF (with cisplatin ≥75/m2) for locally advanced primary HN cancer). The interval from the last cycle of cisplatin and the start of first line treatment for R/M disease is \>6 months.
Overall Response Rate Based on Karnofsky.	41.6 percentage of participants	35.1 percentage of participants	43.7 percentage of participants	34.4 percentage of participants	—	—

SECONDARY outcome

Timeframe: 2 years

Percentage of patients with AEs in relation with total number of treated patients

Outcome measures

Outcome measures
Measure	Arm 1 n=93 Participants NIVOTAX (nivolumab + paclitaxel, follow by maintenance with nivolumab) Nivolumab + Paclitaxel: Combination treatment: Nivolumab 240 mg will be administered via IV infusion every 2 weeks. Paclitaxel 80mg/m2 will be administered via IV infusion weekly. After 12 weeks from the start of the combined treatment paclitaxel will be stopped. Maintenance treatment with nivolumab 480 mg every 4 weeks will start two weeks after the last administration of nivolumab 240 mg. Once nivolumab is administered at 480 mg, paclitaxel can no longer be administered. Nivolumab will be continued alone until disease progression, unacceptable toxicity or withdrawal of consent up to a maximum of 24 months.	Arm 2 n=48 Participants ERBITAX (cetuximab + paclitaxel, follow by maintenance with cetuximab) Cetuximab + Paclitaxel: Combination treatment: Cetuximab 250 mg/m2 (first dose of 400 mg/m2) administered via IV infusion weekly plus weekly paclitaxel (80 mg/m2) administered via IV infusion. After 12 weeks from the start of the combined treatment paclitaxel will be stopped and weekly cetuximab will be continued alone until disease progression, unacceptable toxicity or withdrawal of consent up to a maximum of 24 months.	Arm 2 - CPS <1 ERBITAX - CPS \<1	Arm 2 - CPS >=1 ERBITAX - CPS \>=1	Arm 2 - Group 2 ERBITAX - Group 2 Platinum sensitive but unable for cisplatin based therapy according to one of these criteria: 1. Karnofsky grade 70% or 2. Impaired renal function, creatinine clearance \>30 mL/min and \<80 mL/min GFR could be assessed by direct measurement (EDTA or creatinine clearance) if available or by calculation from serum or plasma creatinine, or 3. Class III heart failure according to the New York Heart Association, or 4. Grade ≥2 hearing loss, according to the NCI CTCAE v 5.0, or 5. History of allergic reactions to cisplatin, carboplatin, or other platinum-containing compounds.	Arm 2 - Group 3 ERBITAX - Group 3 Platinum sensitive but prior dose of cisplatin ≥225 mg/m² for locally advanced disease (one third of the patients - 47 patients) (a patient who received prior RT + 3 cycles of cisplatin 100 mg/m2 or 3 cycles induction TPF (with cisplatin ≥75/m2) for locally advanced primary HN cancer). The interval from the last cycle of cisplatin and the start of first line treatment for R/M disease is \>6 months.
Percentage of Patients With AEs	100 percentage of participants	100 percentage of participants	—	—	—	—

SECONDARY outcome

Timeframe: 2 years

Population: Patients with at least one adverse event G≥3 during study

Percentage of patients with Grade 3 and Grade 4 AEs in relation with total number of treated patients

Outcome measures

Outcome measures
Measure	Arm 1 n=93 Participants NIVOTAX (nivolumab + paclitaxel, follow by maintenance with nivolumab) Nivolumab + Paclitaxel: Combination treatment: Nivolumab 240 mg will be administered via IV infusion every 2 weeks. Paclitaxel 80mg/m2 will be administered via IV infusion weekly. After 12 weeks from the start of the combined treatment paclitaxel will be stopped. Maintenance treatment with nivolumab 480 mg every 4 weeks will start two weeks after the last administration of nivolumab 240 mg. Once nivolumab is administered at 480 mg, paclitaxel can no longer be administered. Nivolumab will be continued alone until disease progression, unacceptable toxicity or withdrawal of consent up to a maximum of 24 months.	Arm 2 n=48 Participants ERBITAX (cetuximab + paclitaxel, follow by maintenance with cetuximab) Cetuximab + Paclitaxel: Combination treatment: Cetuximab 250 mg/m2 (first dose of 400 mg/m2) administered via IV infusion weekly plus weekly paclitaxel (80 mg/m2) administered via IV infusion. After 12 weeks from the start of the combined treatment paclitaxel will be stopped and weekly cetuximab will be continued alone until disease progression, unacceptable toxicity or withdrawal of consent up to a maximum of 24 months.	Arm 2 - CPS <1 ERBITAX - CPS \<1	Arm 2 - CPS >=1 ERBITAX - CPS \>=1	Arm 2 - Group 2 ERBITAX - Group 2 Platinum sensitive but unable for cisplatin based therapy according to one of these criteria: 1. Karnofsky grade 70% or 2. Impaired renal function, creatinine clearance \>30 mL/min and \<80 mL/min GFR could be assessed by direct measurement (EDTA or creatinine clearance) if available or by calculation from serum or plasma creatinine, or 3. Class III heart failure according to the New York Heart Association, or 4. Grade ≥2 hearing loss, according to the NCI CTCAE v 5.0, or 5. History of allergic reactions to cisplatin, carboplatin, or other platinum-containing compounds.	Arm 2 - Group 3 ERBITAX - Group 3 Platinum sensitive but prior dose of cisplatin ≥225 mg/m² for locally advanced disease (one third of the patients - 47 patients) (a patient who received prior RT + 3 cycles of cisplatin 100 mg/m2 or 3 cycles induction TPF (with cisplatin ≥75/m2) for locally advanced primary HN cancer). The interval from the last cycle of cisplatin and the start of first line treatment for R/M disease is \>6 months.
Percentage of Patients With Grade 3 and Grade 4 AEs	72.0 percentage of participants	68.8 percentage of participants	—	—	—	—

SECONDARY outcome

Timeframe: Up to 45 months

Percentage of patients with SAEs in relation with total number of treated patients

Outcome measures

Outcome measures
Measure	Arm 1 n=93 Participants NIVOTAX (nivolumab + paclitaxel, follow by maintenance with nivolumab) Nivolumab + Paclitaxel: Combination treatment: Nivolumab 240 mg will be administered via IV infusion every 2 weeks. Paclitaxel 80mg/m2 will be administered via IV infusion weekly. After 12 weeks from the start of the combined treatment paclitaxel will be stopped. Maintenance treatment with nivolumab 480 mg every 4 weeks will start two weeks after the last administration of nivolumab 240 mg. Once nivolumab is administered at 480 mg, paclitaxel can no longer be administered. Nivolumab will be continued alone until disease progression, unacceptable toxicity or withdrawal of consent up to a maximum of 24 months.	Arm 2 n=48 Participants ERBITAX (cetuximab + paclitaxel, follow by maintenance with cetuximab) Cetuximab + Paclitaxel: Combination treatment: Cetuximab 250 mg/m2 (first dose of 400 mg/m2) administered via IV infusion weekly plus weekly paclitaxel (80 mg/m2) administered via IV infusion. After 12 weeks from the start of the combined treatment paclitaxel will be stopped and weekly cetuximab will be continued alone until disease progression, unacceptable toxicity or withdrawal of consent up to a maximum of 24 months.	Arm 2 - CPS <1 ERBITAX - CPS \<1	Arm 2 - CPS >=1 ERBITAX - CPS \>=1	Arm 2 - Group 2 ERBITAX - Group 2 Platinum sensitive but unable for cisplatin based therapy according to one of these criteria: 1. Karnofsky grade 70% or 2. Impaired renal function, creatinine clearance \>30 mL/min and \<80 mL/min GFR could be assessed by direct measurement (EDTA or creatinine clearance) if available or by calculation from serum or plasma creatinine, or 3. Class III heart failure according to the New York Heart Association, or 4. Grade ≥2 hearing loss, according to the NCI CTCAE v 5.0, or 5. History of allergic reactions to cisplatin, carboplatin, or other platinum-containing compounds.	Arm 2 - Group 3 ERBITAX - Group 3 Platinum sensitive but prior dose of cisplatin ≥225 mg/m² for locally advanced disease (one third of the patients - 47 patients) (a patient who received prior RT + 3 cycles of cisplatin 100 mg/m2 or 3 cycles induction TPF (with cisplatin ≥75/m2) for locally advanced primary HN cancer). The interval from the last cycle of cisplatin and the start of first line treatment for R/M disease is \>6 months.
Percentage of Patients With SAEs	57.0 percentage of participants	54.2 percentage of participants	—	—	—	—

SECONDARY outcome

Timeframe: Up to 2 years

Percentage of patients who discontinued due to AEs in relation with total number of treated patients

Outcome measures

Outcome measures
Measure	Arm 1 n=93 Participants NIVOTAX (nivolumab + paclitaxel, follow by maintenance with nivolumab) Nivolumab + Paclitaxel: Combination treatment: Nivolumab 240 mg will be administered via IV infusion every 2 weeks. Paclitaxel 80mg/m2 will be administered via IV infusion weekly. After 12 weeks from the start of the combined treatment paclitaxel will be stopped. Maintenance treatment with nivolumab 480 mg every 4 weeks will start two weeks after the last administration of nivolumab 240 mg. Once nivolumab is administered at 480 mg, paclitaxel can no longer be administered. Nivolumab will be continued alone until disease progression, unacceptable toxicity or withdrawal of consent up to a maximum of 24 months.	Arm 2 n=59 Participants ERBITAX (cetuximab + paclitaxel, follow by maintenance with cetuximab) Cetuximab + Paclitaxel: Combination treatment: Cetuximab 250 mg/m2 (first dose of 400 mg/m2) administered via IV infusion weekly plus weekly paclitaxel (80 mg/m2) administered via IV infusion. After 12 weeks from the start of the combined treatment paclitaxel will be stopped and weekly cetuximab will be continued alone until disease progression, unacceptable toxicity or withdrawal of consent up to a maximum of 24 months.	Arm 2 - CPS <1 n=48 Participants ERBITAX - CPS \<1	Arm 2 - CPS >=1 n=33 Participants ERBITAX - CPS \>=1	Arm 2 - Group 2 ERBITAX - Group 2 Platinum sensitive but unable for cisplatin based therapy according to one of these criteria: 1. Karnofsky grade 70% or 2. Impaired renal function, creatinine clearance \>30 mL/min and \<80 mL/min GFR could be assessed by direct measurement (EDTA or creatinine clearance) if available or by calculation from serum or plasma creatinine, or 3. Class III heart failure according to the New York Heart Association, or 4. Grade ≥2 hearing loss, according to the NCI CTCAE v 5.0, or 5. History of allergic reactions to cisplatin, carboplatin, or other platinum-containing compounds.	Arm 2 - Group 3 ERBITAX - Group 3 Platinum sensitive but prior dose of cisplatin ≥225 mg/m² for locally advanced disease (one third of the patients - 47 patients) (a patient who received prior RT + 3 cycles of cisplatin 100 mg/m2 or 3 cycles induction TPF (with cisplatin ≥75/m2) for locally advanced primary HN cancer). The interval from the last cycle of cisplatin and the start of first line treatment for R/M disease is \>6 months.
Percentage of Patients Who Discontinued Due to AEs	14.0 percentage of participants	10.2 percentage of participants	10.4 percentage of participants	6.1 percentage of participants	—	—

Adverse Events

Arm 1

Serious events: 53 serious events

Other events: 93 other events

Deaths: 79 deaths

Arm 2

Serious events: 26 serious events

Other events: 48 other events

Deaths: 43 deaths

Serious adverse events

Serious adverse events
Measure	Arm 1 n=93 participants at risk NIVOTAX (nivolumab + paclitaxel, follow by maintenance with nivolumab) Nivolumab + Paclitaxel: Combination treatment: Nivolumab 240 mg will be administered via IV infusion every 2 weeks. Paclitaxel 80mg/m2 will be administered via IV infusion weekly. After 12 weeks from the start of the combined treatment paclitaxel will be stopped. Maintenance treatment with nivolumab 480 mg every 4 weeks will start two weeks after the last administration of nivolumab 240 mg. Once nivolumab is administered at 480 mg, paclitaxel can no longer be administered. Nivolumab will be continued alone until disease progression, unacceptable toxicity or withdrawal of consent up to a maximum of 24 months.	Arm 2 n=48 participants at risk ERBITAX (cetuximab + paclitaxel, follow by maintenance with cetuximab) Cetuximab + Paclitaxel: Combination treatment: Cetuximab 250 mg/m2 (first dose of 400 mg/m2) administered via IV infusion weekly plus weekly paclitaxel (80 mg/m2) administered via IV infusion. After 12 weeks from the start of the combined treatment paclitaxel will be stopped and weekly cetuximab will be continued alone until disease progression, unacceptable toxicity or withdrawal of consent up to a maximum of 24 months.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Angiosarcoma	0.00% 0/93 • Up to 45 months	2.1% 1/48 • Number of events 1 • Up to 45 months
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Bladder cancer	0.00% 0/93 • Up to 45 months	2.1% 1/48 • Number of events 1 • Up to 45 months
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Bladder neoplasm	0.00% 0/93 • Up to 45 months	2.1% 1/48 • Number of events 1 • Up to 45 months
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Colorectal adenocarcinoma	1.1% 1/93 • Number of events 1 • Up to 45 months	0.00% 0/48 • Up to 45 months
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Infected neoplasm	1.1% 1/93 • Number of events 2 • Up to 45 months	0.00% 0/48 • Up to 45 months
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Tumour haemorrhage	3.2% 3/93 • Number of events 3 • Up to 45 months	2.1% 1/48 • Number of events 1 • Up to 45 months
Surgical and medical procedures Gastrostomy	0.00% 0/93 • Up to 45 months	2.1% 1/48 • Number of events 1 • Up to 45 months
Surgical and medical procedures Hernia repair	1.1% 1/93 • Number of events 1 • Up to 45 months	0.00% 0/48 • Up to 45 months
General disorders Asthenia	1.1% 1/93 • Number of events 1 • Up to 45 months	0.00% 0/48 • Up to 45 months
General disorders Death	0.00% 0/93 • Up to 45 months	2.1% 1/48 • Number of events 1 • Up to 45 months
General disorders Disease progression	1.1% 1/93 • Number of events 1 • Up to 45 months	0.00% 0/48 • Up to 45 months
General disorders Face oedema	0.00% 0/93 • Up to 45 months	2.1% 1/48 • Number of events 1 • Up to 45 months
General disorders Impaired healing	1.1% 1/93 • Number of events 1 • Up to 45 months	0.00% 0/48 • Up to 45 months
General disorders Mucosal inflammation	1.1% 1/93 • Number of events 1 • Up to 45 months	2.1% 1/48 • Number of events 1 • Up to 45 months
Immune system disorders Hypersensitivity	0.00% 0/93 • Up to 45 months	2.1% 1/48 • Number of events 1 • Up to 45 months
Respiratory, thoracic and mediastinal disorders Aspiration	1.1% 1/93 • Number of events 1 • Up to 45 months	0.00% 0/48 • Up to 45 months
Respiratory, thoracic and mediastinal disorders Dyspnoea	1.1% 1/93 • Number of events 1 • Up to 45 months	0.00% 0/48 • Up to 45 months
Respiratory, thoracic and mediastinal disorders Pharyngeal haemorrhage	1.1% 1/93 • Number of events 1 • Up to 45 months	0.00% 0/48 • Up to 45 months
Respiratory, thoracic and mediastinal disorders Pneumonitis	1.1% 1/93 • Number of events 1 • Up to 45 months	0.00% 0/48 • Up to 45 months
Respiratory, thoracic and mediastinal disorders Pulmonary embolism	2.2% 2/93 • Number of events 2 • Up to 45 months	2.1% 1/48 • Number of events 1 • Up to 45 months
Respiratory, thoracic and mediastinal disorders Respiratory failure	6.5% 6/93 • Number of events 6 • Up to 45 months	2.1% 1/48 • Number of events 1 • Up to 45 months
Injury, poisoning and procedural complications Accidental overdose	1.1% 1/93 • Number of events 1 • Up to 45 months	0.00% 0/48 • Up to 45 months
Injury, poisoning and procedural complications Craniocerebral injury	1.1% 1/93 • Number of events 1 • Up to 45 months	0.00% 0/48 • Up to 45 months
Injury, poisoning and procedural complications Overdose	1.1% 1/93 • Number of events 2 • Up to 45 months	0.00% 0/48 • Up to 45 months
Injury, poisoning and procedural complications Product administration error	1.1% 1/93 • Number of events 1 • Up to 45 months	2.1% 1/48 • Number of events 1 • Up to 45 months
Injury, poisoning and procedural complications Product dispensing error	2.2% 2/93 • Number of events 2 • Up to 45 months	0.00% 0/48 • Up to 45 months
Injury, poisoning and procedural complications Radiation proctitis	0.00% 0/93 • Up to 45 months	2.1% 1/48 • Number of events 1 • Up to 45 months
Cardiac disorders Cardiac failure	0.00% 0/93 • Up to 45 months	2.1% 1/48 • Number of events 1 • Up to 45 months
Cardiac disorders Myocardial infarction	1.1% 1/93 • Number of events 1 • Up to 45 months	0.00% 0/48 • Up to 45 months
Cardiac disorders Myocarditis	1.1% 1/93 • Number of events 1 • Up to 45 months	0.00% 0/48 • Up to 45 months
Nervous system disorders Hepatic encephalopathy	1.1% 1/93 • Number of events 1 • Up to 45 months	0.00% 0/48 • Up to 45 months
Blood and lymphatic system disorders Anaemia	1.1% 1/93 • Number of events 1 • Up to 45 months	0.00% 0/48 • Up to 45 months
Blood and lymphatic system disorders Febrile neutropenia	0.00% 0/93 • Up to 45 months	2.1% 1/48 • Number of events 1 • Up to 45 months
Blood and lymphatic system disorders Neutropenia	0.00% 0/93 • Up to 45 months	2.1% 1/48 • Number of events 1 • Up to 45 months
Eye disorders Diplopia	1.1% 1/93 • Number of events 1 • Up to 45 months	0.00% 0/48 • Up to 45 months
Gastrointestinal disorders Colitis	0.00% 0/93 • Up to 45 months	2.1% 1/48 • Number of events 1 • Up to 45 months
Gastrointestinal disorders Diarrhoea	1.1% 1/93 • Number of events 1 • Up to 45 months	2.1% 1/48 • Number of events 1 • Up to 45 months
Gastrointestinal disorders Dysphagia	7.5% 7/93 • Number of events 8 • Up to 45 months	2.1% 1/48 • Number of events 2 • Up to 45 months
Gastrointestinal disorders Gastritis	1.1% 1/93 • Number of events 1 • Up to 45 months	0.00% 0/48 • Up to 45 months
Gastrointestinal disorders Mouth haemorrhage	0.00% 0/93 • Up to 45 months	2.1% 1/48 • Number of events 1 • Up to 45 months
Gastrointestinal disorders Oesophagitis	1.1% 1/93 • Number of events 1 • Up to 45 months	0.00% 0/48 • Up to 45 months
Gastrointestinal disorders Stomatitis	1.1% 1/93 • Number of events 1 • Up to 45 months	0.00% 0/48 • Up to 45 months
Gastrointestinal disorders Submaxillary gland enlargement	1.1% 1/93 • Number of events 1 • Up to 45 months	0.00% 0/48 • Up to 45 months
Gastrointestinal disorders Vomiting	0.00% 0/93 • Up to 45 months	4.2% 2/48 • Number of events 2 • Up to 45 months
Hepatobiliary disorders Hepatitis	1.1% 1/93 • Number of events 1 • Up to 45 months	0.00% 0/48 • Up to 45 months
Hepatobiliary disorders Immune-mediated hepatitis	2.2% 2/93 • Number of events 2 • Up to 45 months	0.00% 0/48 • Up to 45 months
Renal and urinary disorders Acute kidney injury	1.1% 1/93 • Number of events 1 • Up to 45 months	0.00% 0/48 • Up to 45 months
Renal and urinary disorders Renal failure	1.1% 1/93 • Number of events 1 • Up to 45 months	0.00% 0/48 • Up to 45 months
Endocrine disorders Hypercalcaemia of malignancy	0.00% 0/93 • Up to 45 months	2.1% 1/48 • Number of events 1 • Up to 45 months
Musculoskeletal and connective tissue disorders Hip fracture	1.1% 1/93 • Number of events 1 • Up to 45 months	0.00% 0/48 • Up to 45 months
Infections and infestations Appendicitis	1.1% 1/93 • Number of events 1 • Up to 45 months	0.00% 0/48 • Up to 45 months
Infections and infestations Cholecystitis infective	1.1% 1/93 • Number of events 1 • Up to 45 months	0.00% 0/48 • Up to 45 months
Infections and infestations Clostridium difficile infection	0.00% 0/93 • Up to 45 months	2.1% 1/48 • Number of events 1 • Up to 45 months
Infections and infestations COVID-19	1.1% 1/93 • Number of events 1 • Up to 45 months	0.00% 0/48 • Up to 45 months
Infections and infestations COVID-19 pneumonia	1.1% 1/93 • Number of events 1 • Up to 45 months	0.00% 0/48 • Up to 45 months
Infections and infestations Device related bacteraemia	0.00% 0/93 • Up to 45 months	2.1% 1/48 • Number of events 1 • Up to 45 months
Infections and infestations Device related infection	1.1% 1/93 • Number of events 1 • Up to 45 months	0.00% 0/48 • Up to 45 months
Infections and infestations Empyema	0.00% 0/93 • Up to 45 months	2.1% 1/48 • Number of events 1 • Up to 45 months
Infections and infestations Infected fistula	0.00% 0/93 • Up to 45 months	2.1% 1/48 • Number of events 1 • Up to 45 months
Infections and infestations Infected skin ulcer	1.1% 1/93 • Number of events 1 • Up to 45 months	0.00% 0/48 • Up to 45 months
Infections and infestations Intervertebral discitis	1.1% 1/93 • Number of events 1 • Up to 45 months	0.00% 0/48 • Up to 45 months
Infections and infestations Klebsiella infection	1.1% 1/93 • Number of events 1 • Up to 45 months	0.00% 0/48 • Up to 45 months
Infections and infestations Pneumonia	9.7% 9/93 • Number of events 9 • Up to 45 months	4.2% 2/48 • Number of events 2 • Up to 45 months
Infections and infestations Pneumonia aspiration	2.2% 2/93 • Number of events 2 • Up to 45 months	0.00% 0/48 • Up to 45 months
Infections and infestations Post procedural infection	1.1% 1/93 • Number of events 1 • Up to 45 months	0.00% 0/48 • Up to 45 months
Infections and infestations Respiratory tract infection	6.5% 6/93 • Number of events 6 • Up to 45 months	12.5% 6/48 • Number of events 6 • Up to 45 months
Infections and infestations Sepsis	3.2% 3/93 • Number of events 3 • Up to 45 months	2.1% 1/48 • Number of events 2 • Up to 45 months
Infections and infestations Septic shock	1.1% 1/93 • Number of events 1 • Up to 45 months	0.00% 0/48 • Up to 45 months
Infections and infestations Stenotrophomonas sepsis	1.1% 1/93 • Number of events 1 • Up to 45 months	0.00% 0/48 • Up to 45 months
Infections and infestations Stoma site cellulitis	1.1% 1/93 • Number of events 1 • Up to 45 months	0.00% 0/48 • Up to 45 months
Infections and infestations Urinary tract infection pseudomonal	0.00% 0/93 • Up to 45 months	2.1% 1/48 • Number of events 1 • Up to 45 months
Metabolism and nutrition disorders Hyperglycaemia	0.00% 0/93 • Up to 45 months	2.1% 1/48 • Number of events 1 • Up to 45 months
Metabolism and nutrition disorders Hyponatraemia	1.1% 1/93 • Number of events 1 • Up to 45 months	0.00% 0/48 • Up to 45 months

Other adverse events

Other adverse events
Measure	Arm 1 n=93 participants at risk NIVOTAX (nivolumab + paclitaxel, follow by maintenance with nivolumab) Nivolumab + Paclitaxel: Combination treatment: Nivolumab 240 mg will be administered via IV infusion every 2 weeks. Paclitaxel 80mg/m2 will be administered via IV infusion weekly. After 12 weeks from the start of the combined treatment paclitaxel will be stopped. Maintenance treatment with nivolumab 480 mg every 4 weeks will start two weeks after the last administration of nivolumab 240 mg. Once nivolumab is administered at 480 mg, paclitaxel can no longer be administered. Nivolumab will be continued alone until disease progression, unacceptable toxicity or withdrawal of consent up to a maximum of 24 months.	Arm 2 n=48 participants at risk ERBITAX (cetuximab + paclitaxel, follow by maintenance with cetuximab) Cetuximab + Paclitaxel: Combination treatment: Cetuximab 250 mg/m2 (first dose of 400 mg/m2) administered via IV infusion weekly plus weekly paclitaxel (80 mg/m2) administered via IV infusion. After 12 weeks from the start of the combined treatment paclitaxel will be stopped and weekly cetuximab will be continued alone until disease progression, unacceptable toxicity or withdrawal of consent up to a maximum of 24 months.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Tumour haemorrhage	5.4% 5/93 • Number of events 6 • Up to 45 months	2.1% 1/48 • Number of events 2 • Up to 45 months
Vascular disorders Hypertension	5.4% 5/93 • Number of events 7 • Up to 45 months	2.1% 1/48 • Number of events 1 • Up to 45 months
General disorders Asthenia	61.3% 57/93 • Number of events 166 • Up to 45 months	60.4% 29/48 • Number of events 61 • Up to 45 months
General disorders Crepitations	0.00% 0/93 • Up to 45 months	8.3% 4/48 • Number of events 5 • Up to 45 months
General disorders Fatigue	11.8% 11/93 • Number of events 22 • Up to 45 months	6.2% 3/48 • Number of events 7 • Up to 45 months
General disorders Mucosal inflammation	16.1% 15/93 • Number of events 32 • Up to 45 months	33.3% 16/48 • Number of events 42 • Up to 45 months
General disorders Oedema peripheral	5.4% 5/93 • Number of events 6 • Up to 45 months	6.2% 3/48 • Number of events 4 • Up to 45 months
General disorders Pain	9.7% 9/93 • Number of events 10 • Up to 45 months	8.3% 4/48 • Number of events 8 • Up to 45 months
General disorders Pyrexia	16.1% 15/93 • Number of events 22 • Up to 45 months	12.5% 6/48 • Number of events 10 • Up to 45 months
Respiratory, thoracic and mediastinal disorders Cough	10.8% 10/93 • Number of events 15 • Up to 45 months	6.2% 3/48 • Number of events 4 • Up to 45 months
Respiratory, thoracic and mediastinal disorders Dysphonia	1.1% 1/93 • Number of events 1 • Up to 45 months	8.3% 4/48 • Number of events 6 • Up to 45 months
Respiratory, thoracic and mediastinal disorders Dyspnoea	11.8% 11/93 • Number of events 16 • Up to 45 months	4.2% 2/48 • Number of events 2 • Up to 45 months
Respiratory, thoracic and mediastinal disorders Productive cough	10.8% 10/93 • Number of events 12 • Up to 45 months	8.3% 4/48 • Number of events 5 • Up to 45 months
Respiratory, thoracic and mediastinal disorders Rhinorrhoea	7.5% 7/93 • Number of events 7 • Up to 45 months	4.2% 2/48 • Number of events 2 • Up to 45 months
Psychiatric disorders Anxiety	6.5% 6/93 • Number of events 6 • Up to 45 months	2.1% 1/48 • Number of events 1 • Up to 45 months
Psychiatric disorders Insomnia	7.5% 7/93 • Number of events 7 • Up to 45 months	0.00% 0/48 • Up to 45 months
Investigations Amylase increased	5.4% 5/93 • Number of events 10 • Up to 45 months	2.1% 1/48 • Number of events 1 • Up to 45 months
Investigations Lipase increased	6.5% 6/93 • Number of events 15 • Up to 45 months	4.2% 2/48 • Number of events 3 • Up to 45 months
Investigations Neutrophil count decreased	4.3% 4/93 • Number of events 9 • Up to 45 months	8.3% 4/48 • Number of events 6 • Up to 45 months
Nervous system disorders Dizziness	6.5% 6/93 • Number of events 8 • Up to 45 months	8.3% 4/48 • Number of events 4 • Up to 45 months
Nervous system disorders Headache	8.6% 8/93 • Number of events 10 • Up to 45 months	4.2% 2/48 • Number of events 4 • Up to 45 months
Nervous system disorders Neuropathy peripheral	10.8% 10/93 • Number of events 14 • Up to 45 months	14.6% 7/48 • Number of events 15 • Up to 45 months
Nervous system disorders Neurotoxicity	23.7% 22/93 • Number of events 38 • Up to 45 months	20.8% 10/48 • Number of events 16 • Up to 45 months
Nervous system disorders Paraesthesia	6.5% 6/93 • Number of events 8 • Up to 45 months	10.4% 5/48 • Number of events 5 • Up to 45 months
Nervous system disorders Syncope	1.1% 1/93 • Number of events 1 • Up to 45 months	6.2% 3/48 • Number of events 3 • Up to 45 months
Blood and lymphatic system disorders Anaemia	44.1% 41/93 • Number of events 86 • Up to 45 months	39.6% 19/48 • Number of events 47 • Up to 45 months
Blood and lymphatic system disorders Neutropenia	18.3% 17/93 • Number of events 37 • Up to 45 months	22.9% 11/48 • Number of events 18 • Up to 45 months
Ear and labyrinth disorders Ear pain	2.2% 2/93 • Number of events 2 • Up to 45 months	6.2% 3/48 • Number of events 4 • Up to 45 months
Gastrointestinal disorders Abdominal pain	3.2% 3/93 • Number of events 3 • Up to 45 months	6.2% 3/48 • Number of events 5 • Up to 45 months
Gastrointestinal disorders Cheilitis	2.2% 2/93 • Number of events 3 • Up to 45 months	8.3% 4/48 • Number of events 7 • Up to 45 months
Gastrointestinal disorders Constipation	24.7% 23/93 • Number of events 29 • Up to 45 months	29.2% 14/48 • Number of events 16 • Up to 45 months
Gastrointestinal disorders Diarrhoea	28.0% 26/93 • Number of events 40 • Up to 45 months	29.2% 14/48 • Number of events 24 • Up to 45 months
Gastrointestinal disorders Dry mouth	5.4% 5/93 • Number of events 7 • Up to 45 months	0.00% 0/48 • Up to 45 months
Gastrointestinal disorders Dysphagia	17.2% 16/93 • Number of events 19 • Up to 45 months	16.7% 8/48 • Number of events 8 • Up to 45 months
Gastrointestinal disorders Nausea	14.0% 13/93 • Number of events 15 • Up to 45 months	12.5% 6/48 • Number of events 6 • Up to 45 months
Gastrointestinal disorders Odynophagia	9.7% 9/93 • Number of events 11 • Up to 45 months	10.4% 5/48 • Number of events 7 • Up to 45 months
Gastrointestinal disorders Vomiting	9.7% 9/93 • Number of events 11 • Up to 45 months	12.5% 6/48 • Number of events 7 • Up to 45 months
Skin and subcutaneous tissue disorders Alopecia	28.0% 26/93 • Number of events 36 • Up to 45 months	12.5% 6/48 • Number of events 8 • Up to 45 months
Skin and subcutaneous tissue disorders Dermatitis	2.2% 2/93 • Number of events 3 • Up to 45 months	6.2% 3/48 • Number of events 3 • Up to 45 months
Skin and subcutaneous tissue disorders Dermatitis acneiform	3.2% 3/93 • Number of events 3 • Up to 45 months	16.7% 8/48 • Number of events 17 • Up to 45 months
Skin and subcutaneous tissue disorders Dry skin	2.2% 2/93 • Number of events 2 • Up to 45 months	14.6% 7/48 • Number of events 9 • Up to 45 months
Skin and subcutaneous tissue disorders Erythema	5.4% 5/93 • Number of events 5 • Up to 45 months	2.1% 1/48 • Number of events 1 • Up to 45 months
Skin and subcutaneous tissue disorders Hypertrichosis	0.00% 0/93 • Up to 45 months	6.2% 3/48 • Number of events 3 • Up to 45 months
Skin and subcutaneous tissue disorders Nail toxicity	1.1% 1/93 • Number of events 1 • Up to 45 months	6.2% 3/48 • Number of events 3 • Up to 45 months
Skin and subcutaneous tissue disorders Pruritus	11.8% 11/93 • Number of events 18 • Up to 45 months	12.5% 6/48 • Number of events 8 • Up to 45 months
Skin and subcutaneous tissue disorders Rash	10.8% 10/93 • Number of events 13 • Up to 45 months	52.1% 25/48 • Number of events 58 • Up to 45 months
Skin and subcutaneous tissue disorders Skin fissures	0.00% 0/93 • Up to 45 months	10.4% 5/48 • Number of events 9 • Up to 45 months
Skin and subcutaneous tissue disorders Skin toxicity	2.2% 2/93 • Number of events 2 • Up to 45 months	18.8% 9/48 • Number of events 14 • Up to 45 months
Endocrine disorders Hypothyroidism	14.0% 13/93 • Number of events 17 • Up to 45 months	6.2% 3/48 • Number of events 4 • Up to 45 months
Musculoskeletal and connective tissue disorders Arthralgia	12.9% 12/93 • Number of events 20 • Up to 45 months	8.3% 4/48 • Number of events 5 • Up to 45 months
Musculoskeletal and connective tissue disorders Back pain	6.5% 6/93 • Number of events 6 • Up to 45 months	4.2% 2/48 • Number of events 3 • Up to 45 months
Musculoskeletal and connective tissue disorders Neck pain	11.8% 11/93 • Number of events 13 • Up to 45 months	6.2% 3/48 • Number of events 3 • Up to 45 months
Infections and infestations Conjunctivitis	0.00% 0/93 • Up to 45 months	12.5% 6/48 • Number of events 7 • Up to 45 months
Infections and infestations COVID-19	3.2% 3/93 • Number of events 3 • Up to 45 months	6.2% 3/48 • Number of events 3 • Up to 45 months
Infections and infestations Oral candidiasis	5.4% 5/93 • Number of events 7 • Up to 45 months	4.2% 2/48 • Number of events 2 • Up to 45 months
Infections and infestations Paronychia	1.1% 1/93 • Number of events 1 • Up to 45 months	10.4% 5/48 • Number of events 8 • Up to 45 months
Infections and infestations Pneumonia	5.4% 5/93 • Number of events 6 • Up to 45 months	0.00% 0/48 • Up to 45 months
Infections and infestations Respiratory tract infection	17.2% 16/93 • Number of events 24 • Up to 45 months	14.6% 7/48 • Number of events 11 • Up to 45 months
Infections and infestations Urinary tract infection	9.7% 9/93 • Number of events 9 • Up to 45 months	8.3% 4/48 • Number of events 6 • Up to 45 months
Metabolism and nutrition disorders Decreased appetite	18.3% 17/93 • Number of events 35 • Up to 45 months	29.2% 14/48 • Number of events 17 • Up to 45 months
Metabolism and nutrition disorders Hyperglycaemia	7.5% 7/93 • Number of events 8 • Up to 45 months	6.2% 3/48 • Number of events 4 • Up to 45 months
Metabolism and nutrition disorders Hypomagnesaemia	6.5% 6/93 • Number of events 8 • Up to 45 months	31.2% 15/48 • Number of events 35 • Up to 45 months

Additional Information

Juan Luis Sanz (MW)

APICES

Phone: +34 918166804

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee
Publication restrictions are in place