Table 1.

Characteristics of included trials

Trial identifier/name	Trial type	Therapy	No. of patients	Trial period	ORR	Inclusion criterion	HPV test	Median follow-up (months)
NCT03082534/not applicable10	Non-randomized, multicenter, phase 2 trial	Cetuximab+pembrolizumab	33	2017–2019	Primary endpoint, per RECIST 1.1 by investigators.	No previous immunotherapy or EGFR inhibition; platinum-resistant or platinum-ineligible.	Oropharyngeal tumors: (methods not specified) by local institution. Non-oropharyngeal tumors: HPV negative.	7.3 (IQR: 3.9–10.9)
NCT03370276/not applicable Cohort A11	Non-randomized, multicenter, phase 1/2 trial	Cetuximab+nivolumab	47*	2017–2019	Secondary endpoint, per RECIST 1.1 (not specified by investigators or central review).	Prior exposure to any systemic therapy including cetuximab or PD-1 inhibitors; platinum resistant.	p16 immunohistochemistry (no other information).	32.1
NCT03370276/not applicable Cohort B11	Non-randomized, multicenter, phase 2 trial	Cetuximab+nivolumab	48†	Not report	Secondary endpoint, per RECIST 1.1 (not specified by investigators or central review).	No systemic therapy.	p16 immunohistochemistry (no other information).	15.9 (95% CI 12.2 to 18.8)‡
NCT02105636/CheckMate 1415 6	Randomized, multicenter, phase 3 trial	Nivolumab versus single-agent systemic therapy	240§	2014–2015	Secondary endpoint, per RECIST 1.1 by investigators.	No previous immunotherapy; platinum resistant.	Oropharyngeal tumors: p16 immunohistochemistry by local institution. Non-oropharyngeal tumors: unknown HPV status.	≥ 24.2¶
NCT02252042/KEYNOTE-0401**	Randomized, multicenter, phase 3 trial	Pembrolizumab versus single-agent systemic therapy	247††	2014–2016	Secondary endpoint, per RECIST 1.1 by central review.	No previous immunotherapy; platinum resistant.	Oropharyngeal tumors: p16 immunohistochemistry by local or central testing. Non-oropharyngeal tumors: HPV negative.	8.4 (range: 3.3–14.5) in the pembrolizumab group
NCT01848834/KEYNOTE-0122	Non-randomized, multicenter, phase 1b trial	Pembrolizumab	60 hours‡‡	2013.6–2013.10	Primary endpoint, per RECIST 1.1 by central review.	No previous immunotherapy.	Oropharyngeal tumors: mostly p16 immunohistochemistry by local institution. Non-oropharyngeal tumors: HPV negative.	13 months (range: 1–26)
NCT01848834/KEYNOTE-012 expansion13	Non-randomized, multicenter, phase 1b trial	Pembrolizumab	132§§	2014–2015	Primary endpoint, per RECIST 1.1 by central review.	No previous immunotherapy.	Oropharyngeal tumors: mostly p16 immunohistochemistry by local institution. Non-oropharyngeal tumors: HPV negative.	9 (IQR: 3–11)
NCT02255097/KEYNOTE-0553	Non-randomized, multicenter, phase 2 trial	Pembrolizumab	171¶¶	2014–2015	Primary endpoint, per RECIST 1.1 by central review.	No previous immunotherapy; platinum-resistant; cetuximab-resistant.	Oropharyngeal tumors: mostly p16 immunohistochemistry by local institution. Non-oropharyngeal tumors: HPV negative.	7 (range: 0–17)

*Forty-three and 45 patients were evaluable for the ORR and the 1-year OS rate analysis, respectively.

†Forty-two and 43 patients were evaluable for the ORR and the 1-year OS rate analysis, respectively.

‡For patients including both cohort A and cohort B, and the duration of follow-up was not reported in the cohort B group.

§Among the 240 patients assigned to receive nivolumab monotherapy (121 to receive standard therapy), 120 patients were included for the ORR and the 1-year OS rate analysis, respectively.

¶For patients in both nivolumab and single-agent systemic therapy group, and the duration of follow-up was not reported in the nivolumab group.

**The relevant data was reported in the documents submitted to the European Medicines Evaluation Agency for approval.24

††The 247 patients were assigned to receive pembrolizumab monotherapy.

‡‡Forty-five and 56 patients were evaluable for the ORR and the 1-year OS rate analysis, respectively.

§§104 patients with tumor location in the oral cavity, oropharynx, larynx, and hypopharynx were included for the ORR analysis, and no data were reported for the 1-year OS rate analysis, respectively.

¶¶168 patients were evaluable for the ORR and the 1-year OS rate analysis, respectively.

CI, confidence interval; EGFR, epidermal growth factor receptor; HPV, human papillomavirus; IQR, interquartile range; ORR, objective response rate; PD-1, programmed cell death protein 1; RECIST v1.1, Response Evaluation Criteria in Solid Tumors, version 1.1.