Assessment of Efficacy and Safety of Monalizumab Plus Cetuximab Compared to Placebo Plus Cetuximab in Recurrent or Metastatic Head and Neck Cancer

Participants with recurrent or metastatic squamous cell carcinoma of the head and neck (SCCHN) who had prior immune checkpoint inhibitor and platinum-based chemotherapy treatment will be randomized in a 2:1 ratio to monalizumab and cetuximab or placebo and cetuximab. Efficacy and safety assessments will be performed periodically from the time of enrollment and throughout the study. Participants in all arms will continue therapy until progression, unacceptable toxicity, withdrawal of consent, or another discontinuation criterion is met. All Participants will be followed for survival after progression is confirmed.

• Monalizumab (Drug), also known as IPH2201: Participants will receive IV infusion of monalizumab as stated in arm description.
• Cetuximab (Drug), also known as Erbitux: Participants will receive IV infusion of cetuximab as stated in arm description.
• Placebo (Other): Participants will receive IV infusion of placebo as stated in arm description.

Primary outcomes

• Overall Survival (OS) in Human Papillomavirus (HPV)-Unrelated Analysis Set [Baseline (-28 to -1) through 17.5 months (maximum observed duration)]: The OS is defined as time from the date of randomization until death due to any cause regardless of whether the participant withdraws from randomized therapy or receives another anti-cancer therapy (i.e. date of death or censoring - date of randomization + 1). The OS was analyzed using Kaplan-Meier technique. Statistical analysis was performed using P-value from a stratified log-rank test and hazard ratio (HR) and confidence intervals (CIs) from a stratified Cox proportional hazards model. Analyses were stratified on World Health Organization/ Eastern Cooperative Oncology Group performance status (WHO/ECOG PS) (0 or 1) and number of prior lines of therapy in recurrent or metastatic (R/M) setting (1 or 2).

Secondary outcomes

• Overall Survival in Full Analysis Set (FAS) [Baseline (-28 to -1) through 17.5 months (maximum observed duration)]: The OS is defined as time from the date of randomization until death due to any cause regardless of whether the participant withdraws from randomized therapy or receives another anti-cancer therapy (i.e. date of death or censoring - date of randomization + 1). The OS was analyzed using Kaplan-Meier technique. Statistical analysis was performed using P-value from a stratified log-rank test and HR and CIs from a stratified Cox proportional hazards model. Analyses were stratified on HPV status (OPC HPV positive or HPV-unrelated), WHO/ECOG PS (0 or 1) and number of prior lines of therapy in R/M setting (1 or 2).
• Progression-Free Survival (PFS) Per Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 by Investigator Assessment in HPV-unrelated Analysis Set [Baseline (-28 to -1) through 17.5 months (maximum observed duration)]: PFS per RECIST 1.1 as assessed by the investigator is defined as time from randomization until date of RECIST 1.1-defined radiological progressive disease (PD) or death regardless of whether participant withdraws from therapy or received subsequent anticancer therapy prior to progression. PD: at least 20% increase in sum of diameters of target lesions (TLs), taking as reference the smallest sum on study (nadir) and sum must demonstrate an absolute increase of at least 5 mm from nadir or unequivocal progression of existing non-TLs (NTLs) or appearance of new lesions. PFS was analyzed using Kaplan-Meier technique. Statistical analysis was performed using P-value from stratified log-rank test and HR and CIs from a stratified Cox proportional hazards model. Analyses were stratified on WHO/ECOG PS (0/1) and no. of prior lines of therapy in R/M setting.
• Progression-Free Survival Per RECIST 1.1 by Investigator Assessment in FAS [Baseline (-28 to -1) through 17.5 months (maximum observed duration)]: PFS per RECIST 1.1 as assessed by the investigator is defined as time from randomization until date of RECIST 1.1-defined radiological progressive disease (PD) or death regardless of whether participant withdraws from therapy or received subsequent anticancer therapy prior to progression. PD: at least 20% increase in sum of diameters of target lesions (TLs), taking as reference the smallest sum on study (nadir) and sum must demonstrate an absolute increase of at least 5 mm from nadir or unequivocal progression of existing NTLs or appearance of new lesions. PFS was analyzed using Kaplan-Meier technique. Statistical analysis was performed using P-value from a stratified log-rank test and HR and CIs from a stratified Cox proportional hazards model. Analyses were stratified on HPV status, WHO/ECOG PS (0/1) and no. of prior lines of therapy in R/M setting.
• Percentage of Participants With Objective Response (OR) Per RECIST 1.1 in HPV-unrelated Analysis Set [Baseline (-28 to -1) through 17.5 months (maximum observed duration)]: The OR is defined as the percentage of participants with at least one confirmed investigator-assessed response of complete response (CR) or partial response (PR) as assessed by RECIST 1.1 guidelines. The CR is defined as disappearance of all TLs and NTLs, any pathological lymph nodes (target and non-target) must have reduction in short axis < 10 mm, and no new lesions. The PR is defined as at least a 30% decrease in the sum of the diameters (SoD) of TLs (compared to baseline) and no new lesions. Confirmation of CR and PR is required by a repeat, consecutive assessment no less than 4 weeks from the date of first documentation. Percentage of participants with OR is reported. Participants who had measurable disease at baseline per the site investigator were analyzed for this outcome.
• Percentage of Participants With OR Per RECIST 1.1 in FAS [Baseline (-28 to -1) through 17.5 months (maximum observed duration)]: The OR is defined as the percentage of participants with at least one confirmed investigator-assessed response of CR or PR as assessed by RECIST 1.1 guidelines. The CR is defined as disappearance of all TLs and NTLs, any pathological lymph nodes (target and non-target) must have reduction in short axis < 10 mm, and no new lesions. The PR is defined as at least a 30% decrease in the SoD of TLs (compared to baseline) and no new lesions. Confirmation of CR and PR is required by a repeat, consecutive assessment no less than 4 weeks from the date of first documentation. Percentage of participants with OR is reported. Participants who had measurable disease at baseline per the site investigator were analyzed for this outcome.
• Duration of Response (DoR) Per RECIST 1.1 in HPV-unrelated Analysis Set [Baseline (-28 to -1) through 17.5 months (maximum observed duration)]: The DoR is defined as the time from the date of first documented confirmed response until date of documented progression or death in the absence of disease progression (i.e. date of PFS event or censoring - date of first response + 1). The CR is defined as disappearance of all target and non-target lesions, no new lesions, and normalization of tumor marker level. The PR is defined as at least a 30% decrease in the SoDs of TLs (compared to baseline) and no new lesions. Confirmation of CR and PR is required by a repeat, consecutive assessment no less than 4 weeks from the date of first documentation. The PD is defined as at least a 20% increase in the SoDs of TLs, taking as reference the smallest previous SoDs (nadir) and the sum must demonstrate an absolute increase of at least 5 mm from nadir or unequivocal progression of existing NTLs or appearance of new lesions. The DoR was analyzed using Kaplan-Meier technique.
• Duration of Response Per RECIST 1.1 in FAS [Baseline (-28 to -1) through 17.5 months (maximum observed duration)]: The DoR is defined as the time from the date of first documented confirmed response until date of documented progression or death in the absence of disease progression (i.e. date of PFS event or censoring - date of first response + 1). The CR is defined as disappearance of all target and non-target lesions, no new lesions, and normalization of tumor marker level. The PR is defined as at least a 30% decrease in the SoDs of TLs (compared to baseline) and no new lesions. Confirmation of CR and PR is required by a repeat, consecutive assessment no less than 4 weeks from the date of first documentation. The PD is defined as at least a 20% increase in the SoDs of TLs, taking as reference the smallest previous SoDs (nadir) and the sum must demonstrate an absolute increase of at least 5 mm from nadir or unequivocal progression of existing NTLs or appearance of new lesions. The DoR was analyzed using Kaplan-Meier technique.
• Number of Participants With Treatment-emergent Adverse Events (TEAEs) [Day 1 through 21.4 months (maximum observed duration)]: An adverse event (AE) is any untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship. TEAEs included events from the first dose of study drug, up to 90 days after the last dose of study drug received or up to the start date of any subsequent anticancer therapy following discontinuation of study drug, or the final safety DCO date of 01Sep2022, whichever occurred first.
• Number of Participants With Abnormal Clinical Laboratory Parameters Reported as TEAEs [Day 1 through 21.4 months (maximum observed duration)]: Participants with abnormal laboratory parameters reported as TEAEs are reported. Laboratory analysis included hematology and clinical chemistry. TEAEs included events from the first dose of study drug, up to 90 days after the last dose of study drug received or up to the start date of any subsequent anticancer therapy following discontinuation of study drug, or the final safety DCO date of 01Sep2022, whichever occurred first.
• Number of Participants With Abnormal Vital Signs Reported as TEAEs [Day 1 through 21.4 months (maximum observed duration)]: Participants with abnormal vital signs (heart rate, blood pressure, temperature, and respiratory rate) reported as TEAEs are reported. TEAEs included events from the first dose of study drug, up to 90 days after the last dose of study drug received or up to the start date of any subsequent anticancer therapy following discontinuation of study drug, or the final safety DCO date of 01Sep2022, whichever occurred first.
• Number of Participants With Electrocardiograms (ECGs) Reported as TEAEs [Day 1 through 21.4 months (maximum observed duration)]: Participants with Abnormal ECGs reported as TEAEs are reported. TEAEs included events from the first dose of study drug, up to 90 days after the last dose of study drug received or up to the start date of any subsequent anticancer therapy following discontinuation of study drug, or the final safety DCO date of 01Sep2022, whichever occurred first.

Sex: All, ages: 18 Years to 130 Years

Inclusion Criteria:

* Are aged 18 years and over
* Recurrent or metastatic squamous cell carcinoma of the SCCHN, oral cavity, oropharynx, hypopharynx, or larynx which has progressed on or after previous systemic cancer therapy and is not amenable to curative therapy
* Received prior treatment using a programmed cell death ligand-1 (PD-L1) inhibitor
* Prior platinum failure
* Received 1 or 2 prior systemic regimens for recurrent or metastatic SCCHN
* Has measurable disease per RECIST 1.1
* A fresh or recently acquired tumor tissue for the purpose of biomarker testing
* World Health Organization (WHO)/ Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 or 1

Exclusion Criteria:

* Head and neck cancer of any primary anatomic location in the head and neck not specified in the inclusion criteria, including participants with SCCHN of unknown primary or non-squamous histologies
* Had prior cetuximab therapy (unless it was administered in curative locally advanced setting with radiotherapy and no disease progression for at least 6 months following the last cetuximab dose)
* Active or prior documented autoimmune or inflammatory disorders (including inflammatory bowel disease \[eg, colitis or Crohn's disease\], diverticulitis
* Any concurrent anticancer treatment, except for hormonal therapy for non-cancer-related conditions (eg, hormone replacement therapy)

Participant flow

Outcome results

• Overall Survival (OS) in Human Papillomavirus (HPV)-Unrelated Analysis Set (Primary), Median, Months: Monalizumab 750 mg Q2W + Cetuximab 400 mg/m^2 8.8 (6.9 to 10.4); Placebo Q2W + Cetuximab 400 mg/m^2 8.6 (6.0 to 14.5) (p 0.989)
• Overall Survival in Full Analysis Set (FAS) (Secondary), Median, Months: Monalizumab 750 mg Q2W + Cetuximab 400 mg/m^2 8.8 (6.9 to 10.8); Placebo Q2W + Cetuximab 400 mg/m^2 8.9 (6.0 to 15.1) (p 0.891)
• Progression-Free Survival (PFS) Per Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 by Investigator Assessment in HPV-unrelated Analysis Set (Secondary), Median, Months: Monalizumab 750 mg Q2W + Cetuximab 400 mg/m^2 3.6 (3.1 to 3.7); Placebo Q2W + Cetuximab 400 mg/m^2 3.8 (2.4 to 4.9) (p 0.574)
• Progression-Free Survival Per RECIST 1.1 by Investigator Assessment in FAS (Secondary), Median, Months: Monalizumab 750 mg Q2W + Cetuximab 400 mg/m^2 3.5 (2.3 to 3.7); Placebo Q2W + Cetuximab 400 mg/m^2 3.7 (2.2 to 4.2) (p 0.530)
• Percentage of Participants With Objective Response (OR) Per RECIST 1.1 in HPV-unrelated Analysis Set (Secondary), Number, Percentage of Participants: Monalizumab 750 mg Q2W + Cetuximab 400 mg/m^2 15.2 (0.274 to 1.154); Placebo Q2W + Cetuximab 400 mg/m^2 23.9 (p 0.115)
• Percentage of Participants With OR Per RECIST 1.1 in FAS (Secondary), Number, Percentage of Participants: Monalizumab 750 mg Q2W + Cetuximab 400 mg/m^2 13.1 (0.297 to 1.231); Placebo Q2W + Cetuximab 400 mg/m^2 19.1 (p 0.162)
• Duration of Response (DoR) Per RECIST 1.1 in HPV-unrelated Analysis Set (Secondary), Median, Months: Monalizumab 750 mg Q2W + Cetuximab 400 mg/m^2 5.7 (5.5 to 8.1); Placebo Q2W + Cetuximab 400 mg/m^2 5.6 (4.4 to NA)
• Duration of Response Per RECIST 1.1 in FAS (Secondary), Median, Months: Monalizumab 750 mg Q2W + Cetuximab 400 mg/m^2 5.7 (5.3 to 8.1); Placebo Q2W + Cetuximab 400 mg/m^2 5.6 (4.4 to NA)
• Number of Participants With Treatment-emergent Adverse Events (TEAEs) (Secondary), Count of participants, Participants: Monalizumab 750 mg Q2W + Cetuximab 400 mg/m^2 236; Placebo Q2W + Cetuximab 400 mg/m^2 120
• Number of Participants With Abnormal Clinical Laboratory Parameters Reported as TEAEs (Secondary), Count of participants, Participants: Monalizumab 750 mg Q2W + Cetuximab 400 mg/m^2 35; Placebo Q2W + Cetuximab 400 mg/m^2 15
• Number of Participants With Abnormal Vital Signs Reported as TEAEs (Secondary), Count of participants, Participants: Monalizumab 750 mg Q2W + Cetuximab 400 mg/m^2 4; Placebo Q2W + Cetuximab 400 mg/m^2 4
• Number of Participants With Electrocardiograms (ECGs) Reported as TEAEs (Secondary), Count of participants, Participants: Monalizumab 750 mg Q2W + Cetuximab 400 mg/m^2 1; Placebo Q2W + Cetuximab 400 mg/m^2 0

Adverse events

Time frame: Day 1 through 21.4 months (maximum observed duration)

Serious adverse events by term

28 more terms not shown.

Other adverse events by term

Limitations and caveats: Study enrolment was discontinued after the planned initial interim futility analysis (IA1) due to unlikelihood of achieving statistical significance for OS in the primary endpoint (HPV-unrelated). Therefore, symptoms, function, health-related quality of life (HRQoL), European Organization for Research and Treatment of Cancer (EORTC) scale/item score, pharmacokinetic (PK) parameters, immunogenicity, human leukocyte antigen E (HLA-E), and NKp46+ expression outcomes were not evaluated.

27 more sites not listed.

• Results publication: Nowojewski A, Wheal A, Dott W, Ruscica D, Ghiorghiu S, Valastro B. Implementation of the Study Participant Feedback Questionnaire to understand participant experience in a phase 3 oncology clinical trial. BMJ Open. 2025 Oct 28;15(10):e094596. doi: 10.1136/bmjopen-2024-094596. PMID 41151963

• Study Protocol (PDF, 2021-07-07)
• Statistical Analysis Plan (PDF, 2022-07-19)

• Roger B Cohen, MD, Principal investigator, Abramson Cancer Center, Perelman Center for Advanced Medicine
• Jérôme Fayette, MD, Principal investigator, Centre Leon Berard
• Dario Ruscica, MD, Study director, AstraZeneca, Cambridge, UK

NIH grants: 2019