CompletedNCT03258554Updated Aug 27, 2026Results posted

Radiation Therapy With Durvalumab or Cetuximab in Treating Patients With Locoregionally Advanced Head and Neck Cancer Who Cannot Take Cisplatin

A Phase 2/3 interventional study of Cetuximab and Durvalumab in Clinical Stage III HPV-Mediated (p16-Positive) Oropharyngeal Carcinoma AJCC v8, Head and Neck Squamous Cell Carcinoma and Hypopharyngeal Squamous Cell Carcinoma, sponsored by National Cancer Institute (NCI). Completed at 256 sites in 2 countries. Open to participants aged 18 Years and older. Per ClinicalTrials.gov, last updated 2026-08-27.

Sponsored by National Cancer Institute (NCI) · Phase 2/3, Interventional, and Treatment

Phase: Phase 2/3
Study type: Interventional
Enrollment: 196
Allocation: Randomized
Ages: 18 Years and older
Sex: All

Study summary

This phase II/III trial studies how well radiation therapy works with durvalumab or cetuximab in treating patients with head and neck cancer that has spread to a local and/or regional area of the body who cannot take cisplatin. Radiation therapy uses high energy x-rays to kill tumor cells and shrink tumors. Immunotherapy with monoclonal antibodies, such as durvalumab, may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread. Cetuximab is a monoclonal antibody that may interfere with the ability of tumor cells to grow and spread. It is not known if radiation therapy with durvalumab will work better than the usual therapy of radiation therapy with cetuximab in treating patients with head and neck cancer.

Read the detailed description

PRIMARY OBJECTIVES:

I. To determine the safety of radiotherapy (RT) with concurrent and adjuvant anti-PD-L1 therapy (MEDI4736 [durvalumab]) is safe in patients with locoregionally advanced head and neck cancer (HNC) who have a contraindication to cisplatin. (Lead-in) II. To test the hypothesis that concurrent RT and anti-PD-L1 therapy improves progression free survival (PFS) compared to standard therapy (RT with concurrent cetuximab) in patients with locoregionally advanced HNC who have a contraindication to cisplatin. (Phase II) III. To test the hypothesis that concurrent RT and anti-PD-L1 therapy improves overall survival compared to standard therapy (RT with concurrent cetuximab) in patients with locoregionally advanced HNC who have a contraindication to cisplatin. (Phase III)

SECONDARY OBJECTIVES:

I. To compare toxicity using Common Terminology Criteria for Adverse Events (CTCAE) and Patient Reported Outcomes (PRO)-CTCAE between patients treated with RT + anti-PD-L1 therapy versus RT/cetuximab.

II. To test the effect of anti-PD-L1 therapy in the subpopulation of patients with tumors that overexpress PD-L1.

III. To compare overall survival, response (at 4-month fludeoxyglucose F-18 [FDG]-positron emission tomography [PET]-computed tomography [CT]), locoregional failure, distant metastasis, and competing mortality in the two arms by known risk factors, including p16 status and omega score.

IV. To test the hypothesis that MEDI4736 (durvalumab) therapy arm will have less decline in the physical function domain of European Organization for Research and Treatment of Cancer Core Questionnaire (EORTC QLQ-C30 version 3.0) based on the change in score from baseline to 12 months from end of RT, compared to the cetuximab-RT arm in patients with locoregionally advanced HNC who have a contraindication to cisplatin.

V. To test the hypothesis that MEDI4736 (durvalumab) therapy arm at 1 year (from end of RT) will have less decline in swallowing related quality of life (QOL) using the M. D. Anderson Dysphagia Inventory (MDADI) total composite score, based on the change in score from baseline to 12 months from end of RT, compared to the cetuximab-RT arm in patients who are medically unfit for cisplatin.

VI. To compare swallowing related performance and function short and long term using the Performance Status Scale for Head \& Neck Cancer Patients (PSS-HN).

VII. To evaluate gastrostomy tube retention rates between arms.

EXPLORATORY OBJECTIVES:

I. To test the hypothesis that radiation combined with MEDI4736 (durvalumab) enhances the adaptive immune response using three types of immunophenotyping compared to radiation combined with cetuximab.

II. To compare overall QOL short term (end RT-8 months) and long term (12-24 months from end of RT) between arms using the EORTC QLQ-C30 version 3.0/HN35.

III. To evaluate swallowing related QOL short term (end RT-8 months) and long term (12-24 months from end of RT) using the EORTC Head and Neck (HN)35 swallowing domain and MDADI (subscales) between arms in patients with locoregionally advanced HNC who have a contraindication to cisplatin.

IV. To evaluate patient reported fatigue using the fatigue items in the EORTC QLQ and PRO-CTCAE.

V. To compare clinician and patient reported toxicity using CTCAE and PRO CTCAE.

VI. To explore health utilities between cetuximab and MEDI4736 (durvalumab) RT using the European Quality of Life 5 Dimensional-5 Level (EQ5D-5L).

OUTLINE: Patients are randomized to 1 of 2 arms.

ARM I: Patients receive cetuximab intravenously (IV) weekly over 60-120 minutes. Treatment repeats every week for up to 8 cycles in the absence of disease progression or unacceptable toxicity. Beginning 5-7 days after first cetuximab dose, patients undergo intensity modulated radiation therapy (IMRT) 5 fractions per week for up to 7 weeks.

ARM II: Patients receive durvalumab IV over 60 minutes every 4 weeks. Treatment repeats every 4 weeks for up to 7 cycles in the absence of disease progression or unacceptable toxicity. Beginning week 2, patients undergo IMRT 5 fractions per week for up to 7 weeks.

After completion of study treatment, patients are followed up at 1 month, every 4 months for 1 year, every 6 months for 2 years, then annually thereafter.

Conditions studied

Clinical Stage III HPV-Mediated (p16-Positive) Oropharyngeal Carcinoma AJCC v8
Head and Neck Squamous Cell Carcinoma
Hypopharyngeal Squamous Cell Carcinoma
Laryngeal Squamous Cell Carcinoma
Oral Cavity Squamous Cell Carcinoma
Oropharyngeal Squamous Cell Carcinoma
Pathologic Stage III HPV-Mediated (p16-Positive) Oropharyngeal Carcinoma AJCC v8
Squamous Cell Carcinoma of Unknown Primary
Stage III Hypopharyngeal Carcinoma AJCC v8
Stage III Laryngeal Cancer AJCC v8
Stage III Lip and Oral Cavity Cancer AJCC v8
Stage III Oropharyngeal (p16-Negative) Carcinoma AJCC v8
Stage IVA Hypopharyngeal Carcinoma AJCC v8
Stage IVA Laryngeal Cancer AJCC v8
Stage IVA Lip and Oral Cavity Cancer AJCC v8
Stage IVA Oropharyngeal (p16-Negative) Carcinoma AJCC v8
Stage IVB Hypopharyngeal Carcinoma AJCC v8
Stage IVB Laryngeal Cancer AJCC v8
Stage IVB Lip and Oral Cavity Cancer AJCC v8
Stage IVB Oropharyngeal (p16-Negative) Carcinoma AJCC v8

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Who can participate

Ages eligible: 18 Years and older
Sexes eligible: All
Accepts healthy volunteers: No

Inclusion criteria

PRIOR TO STEP 1 REGISTRATION INCLUSION CRITERIA
Patients must have pathologically confirmed, previously untreated, unresected squamous cell carcinoma of the larynx, hypopharynx, oropharynx, oral cavity, or carcinoma of unknown head/neck primary prior to step 1 registration; submission of hematoxylin and eosin (H\&E) stained slides and formalin-fixed and paraffin-embedded (FFPE) tissue block (or punch biopsy of FFPE block) to the biospecimen bank at University of California, San Francisco (UCSF) for central review for oropharyngeal and unknown primaries and for p16 analysis for all other non-oropharyngeal primaries is mandatory for all patients; investigators should check with their pathology department regarding release of biospecimens before approaching patients about participation in the trial; for oropharyngeal and unknown primaries, submission of H\&E and p16 stained slides (with the required block for PD-L1) to the biospecimen bank at UCSF for central review is also required prior to step 2 registration
- Note: fine needle aspirates (FNA) samples are not acceptable since they do not provide enough material for PD-L1 and p16 testing; however, if a cell block derived from the FNA is available, it is allowable if there are sufficient cells present in the block for PD-L1 testing; Dr. Jordan will determine this upon receipt; for sites submitting FNA cell blocks for ALL patients they must do so within 7-10 business days from registering the patient; sites must confirm with their cytology/pathology labs to make sure they can provide the required material as the bank must be able to retain these samples for the mandatory testing
Patients must have locoregionally advanced head and neck squamous cell carcinoma (HNSCC)
- For p16-positive oropharyngeal/unknown primaries, American Joint Committee on Cancer [AJCC] 8th edition stage III and selected stage I-II based on smoking status in pack-years
- For laryngeal, hypopharyngeal, and oral cavity primaries and p16-negative oropharyngeal/unknown primaries, AJCC 8th edition stage III-IVB
- Based on the following minimum diagnostic workup within 60 days prior to step 1 registration:
  - General history and physical examination by a radiation oncologist or medical oncologist or ear, nose and throat (ENT) or head \& neck surgeon
  - For larynx, hypopharynx, and base of tongue primaries, a laryngopharyngoscopy (mirror and/or fiberoptic and/or direct procedure) is required, unless the patient cannot tolerate or refuses
- Imaging of the head and neck with a neck CT or magnetic resonance imaging (MRI) (with contrast, unless contraindicated) or PET/CT; note that the CT portion of the PET/CT must be of diagnostic quality, including contrast administration unless contraindicated. If the CT portion of the PET/CT study is low-dose (non-diagnostic), then an additional CT or MRI study with contrast (unless contraindicated) is required
- Chest imaging: chest CT with and without contrast (unless contraindicated) or PET/CT
Patients must have a contraindication to cisplatin as defined in the following bullet points; sites must complete the online tool at comogram.org prior to step 1 registration to determine if the patient is eligible; the scores must be recorded on a case report form (CRF)
- Age >= 70 with moderate to severe comorbidity or vulnerability to cisplatin, defined as having one or more of the following conditions within 30 days prior to step 1 registration:
  - Modified Charlson Comorbidity Index >= 1
  - Adult Comorbidity Evaluation (ACE)-27 Index >= 1
  - Generalized Competing Event Model for Cancer Risk (GCE) omega PFS score \< 0.80
  - Geriatric screening (G-8) score =\< 14
  - Cancer and Aging Research Group (CARG) toxicity score >= 30%
  - Cumulative Illness Rating scale for Geriatrics (CIRS-G) score >= 4 OR
- Age \< 70 with severe comorbidity or vulnerability to cisplatin, defined as having two or more of the following conditions within 30 days prior to step 1 registration
  - Modified Charlson Comorbidity Index >= 1
  - ACE-27 Index >= 1
  - GCE omega PFS-score \< 0.80
  - G-8 score =\< 14
  - CARG Toxicity score >= 30%
  - CIRS-G score >= 4 OR
- Age >= 18 with an absolute or relative contraindication to cisplatin, defined as one or more of the following within 30 days prior to step 1 registration:
  - Creatinine clearance (CC) > 30 and \< 60 cc/min; for this calculation, use the Cockcroft-Gault formula
  - Zubrod performance status 2 prior to step 1 registration
  - Pre-existing peripheral neuropathy grade >= 1
  - History of hearing loss, defined as either:
    - Existing need of a hearing aid OR
    - >= 25 decibel shift over 2 contiguous frequencies on a pretreatment hearing test as clinically indicated
Absolute neutrophil count (ANC) >= 1,000 cells/mm\^3 (within 14 days prior to step 1 registration)
Platelets >= 100,000 cells/mm\^3 (within 14 days prior to step 1 registration)
Hemoglobin >= 9.0 g/dl (Note: the use of transfusion or other intervention to achieve hemoglobin [Hgb] >= 9.0 g/dl is acceptable) (within 14 days prior to step 1 registration)
Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) =\< 2.5 times institutional upper limit of normal (within 14 days prior to step 1 registration)
Serum bilirubin =\< 1.5 x institutional upper limit of normal (within 14 days prior to step 1 registration)
Measured creatinine clearance (CL) > 30 mL/min or calculated creatinine CL > 30 mL/min by the Cockcroft-Gault formula (Cockcroft and Gault 1976) or by 24-hour urine collection for determination of creatinine clearance (within 14 days prior to step 1 registration)
For women of childbearing potential, a negative serum or urine pregnancy test within 14 days prior to step 1 registration; Note: women will be considered post-menopausal if they have been amenorrheic for 12 months without an alternative medical cause; the following age-specific requirements apply:
- Women \< 50 years of age would be considered post-menopausal if they have been amenorrheic for 12 months or more following cessation of exogenous hormonal treatments and if they have luteinizing hormone and follicle-stimulating hormone levels in the post-menopausal range for the institution or underwent surgical sterilization (bilateral oophorectomy or hysterectomy)
- Women >= 50 years of age would be considered post-menopausal if they have been amenorrheic for 12 months or more following cessation of all exogenous hormonal treatments, had radiation-induced menopause with last menses > 1 year ago, had chemotherapy-induced menopause with last menses > 1 year ago, or underwent surgical sterilization (bilateral oophorectomy, bilateral salpingectomy or hysterectomy)
The patient or a legally authorized representative must provide study-specific informed consent prior to step 1 registration
PRIOR TO STEP 2 REGISTRATION INCLUSION CRITERIA
For patients with oropharyngeal or unknown primaries: p16 determination by immunohistochemistry (defined as greater than 70% strong nuclear or nuclear and cytoplasmic staining of tumor cells), confirmed by central pathology review
- Note: for patients with oral cavity, laryngeal, and hypopharyngeal primaries, analysis of p16 status prior to step 2 registration/randomization is not required (p16 status will be analyzed centrally post-hoc); step 2 registration for these patients can be completed after step 1 registration

Exclusion criteria

Exclusion Criteria:

PRIOR TO STEP 1 REGISTRATION EXCLUSION CRITERIA
Prior invasive malignancy within the past 3 years (except for non-melanomatous skin cancer, and early stage treated prostate cancer); synchronous head and neck primaries are ineligible
Prior radiotherapy to the region of the study cancer that would result in overlap of radiation therapy fields
- Note: Prior external beam radiotherapy is excluded, but iodine 131 is allowed
Prior immunotherapy
Prior systemic therapy, including cytotoxic chemotherapy, biologic/targeted therapy, or immune therapy for the study cancer
Major surgery within 28 days prior to step 1 registration
Proven evidence of distant metastases
If both of the following conditions are present, the patient is ineligible:
- =\< 10 pack-year smoking history
- p16-positive carcinoma of the oropharynx or unknown primary that are T0-3, N0-1 (AJCC 8th Edition)
  - Note: in the event that a registered patient with =\< 10 pack-years has a p16-positive result on central review with the tumor and nodal stage T0-3, N0-1 (AJCC 8th Edition), then the site will be notified that the patient is ineligible
Zubrod performance status >= 3
Body weight =\< 30 kg
Patients with oral cavity cancer are excluded from participation if the patient is medically operable and resection of the primary tumor is considered technically feasible by an oral or head and neck cancers surgical subspecialist;(please consult the surgical oncology co-principal investigator [PI], Steven Chang, Doctor of Medicine [MD], if clarification is needed on an individual case)
Sodium \< 130 mmol/L or > 155 mmol/L (within 14 days of step 1 registration, unless corrected prior to step 1 registration)
Potassium \< 3.5 mmol/L or > 6 mmol/L (within 14 days of step 1 registration, unless corrected prior to step 1 registration)
Fasting glucose \< 40 mg/dl or > 400 mg/dl (within 14 days of step 1 registration, unless corrected prior to step 1 registration)
Serum calcium (ionized or adjusted for albumin) \< 7 mg/dl or > 12.5 mg/dl (within 14 days of step 1 registration, unless corrected prior to step 1 registration)
Magnesium \< 0.9 mg/dl or > 3 mg/dl (within 14 days of step 1 registration, unless corrected prior to step 1 registration)
Unstable angina and/or congestive heart failure requiring hospitalization within 3 months prior to step 1 registration
Transmural myocardial infarction within 3 months prior to step 1 registration
Respiratory illness requiring hospitalization at the time of step 1 registration
- Note: if the respiratory illness is resolved and the patient meets the eligibility status above, then the patient can be considered for the trial
Idiopathic pulmonary fibrosis or other severe interstitial lung disease that requires oxygen therapy or is thought to require oxygen therapy within 1 year prior to step 1 registration
History of (non-infectious) pneumonitis that required steroids or current pneumonitis
Clinically apparent jaundice and/or known coagulation defects
Active or prior documented autoimmune or inflammatory disorders (including inflammatory bowel disease [e.g., colitis or Crohn's disease], diverticulitis [with the exception of diverticulosis], systemic lupus erythematosus, Sarcoidosis syndrome, or Wegener syndrome [granulomatosis with polyangiitis], Graves' disease, rheumatoid arthritis, hypophysitis, uveitis, etc.)
- The following are exceptions to this criterion:
  - Patients with vitiligo or alopecia;
  - Patients with hypothyroidism (e.g., following Hashimoto syndrome) stable on hormone replacement;
  - Any chronic skin condition that does not require systemic therapy;
  - Patients without active disease in the last 5 years may be included but only after consultation with the medical oncology study chair;
  - Patients with celiac disease controlled by diet alone
History of active primary immunodeficiency including, but not limited to acquired immune deficiency syndrome (AIDS) based upon current Centers for Disease Control and Prevention (CDC) definition; Note: human immunodeficiency virus (HIV) testing is not required for entry into this protocol; the need to exclude patients with AIDS from this protocol is necessary because the treatment involved in this protocol may be immunosuppressive; patients with known HIV, CD4 counts >= 200/uL, and undetectable viral loads who are stable on an antiretroviral regimen may be included
Current or prior use of immunosuppressive medication within 14 days before step 1 registration, with the exceptions of intranasal and inhaled corticosteroids or systemic corticosteroids at physiological doses, which are not to exceed 10 mg/day of prednisone, or an equivalent corticosteroid
Receipt of live attenuated vaccination within 30 days prior to step 1 registration
Medical or psychiatric illness which would compromise the patient's ability to tolerate treatment or limit compliance with study requirements
Pregnancy or women of childbearing potential and men who are sexually active and not willing/able to use medically acceptable forms of contraception during treatment and for 6 months after the last dose of cetuximab or MEDI14736 (durvalumab); this exclusion is necessary because the treatment involved in this study may be significantly teratogenic; women who are breastfeeding are also excluded
Prior allergic reaction or hypersensitivity to cetuximab or MEDI4736 (durvalumab) or any of study drug excipients
History of allogenic organ transplantation
Uncontrolled hypertension
Uncontrolled cardiac arrhythmia
Uncontrolled serious chronic gastrointestinal condition associated with diarrhea
Active infection including tuberculosis (clinical evaluation that includes clinical history, physical examination and radiographic findings, and tuberculosis [TB] testing in line with local practice), hepatitis B (known positive hepatitis B virus [HBV] surface antigen [HBsAg] result), hepatitis C; patients with a past or resolved HBV infection (defined as the presence of hepatitis B core antibody [anti-HBc] and absence of HBsAg) are eligible; patients positive for hepatitis C (hepatitis C virus [HCV]) antibody are eligible only if polymerase chain reaction is negative for HCV ribonucleic acid (RNA)

Study design

Phase: Phase 2 / Phase 3
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel assignment
Masking: None (open label)
Enrollment: 196 participants (actual)

Study arms

Active comparator
Arm I (cetuximab, radiation therapy)
Patients receive cetuximab IV weekly over 60-120 minutes. Treatment repeats every week for up to 8 cycles in the absence of disease progression or unacceptable toxicity. Beginning 5-7 days after first cetuximab dose, patients undergo IMRT 5 fractions per week for up to 7 weeks.
Biological: Cetuximab · Radiation: Intensity-Modulated Radiation Therapy · Other: Laboratory Biomarker Analysis · Other: Quality-of-Life Assessment · Other: Questionnaire Administration
Experimental
Arm II (durvalumab, radiation therapy)
Patients receive durvalumab IV over 60 minutes every 4 weeks. Treatment repeats every 4 weeks for up to 7 cycles in the absence of disease progression or unacceptable toxicity. Beginning week 2, patients undergo IMRT 5 fractions per week for up to 7 weeks.
Biological: Durvalumab · Radiation: Intensity-Modulated Radiation Therapy · Other: Laboratory Biomarker Analysis · Other: Quality-of-Life Assessment · Other: Questionnaire Administration

Interventions

BiologicalCetuximab
Given IV
Also known as: C 225, C-225, C225, Cetuximab Biosimilar CDP-1, Cetuximab Biosimilar CMAB009, Cetuximab Biosimilar KL 140, Chimeric Anti-EGFR Monoclonal Antibody, Chimeric MoAb C225, Chimeric Monoclonal Antibody C225, Erbitux, IMC-C225
BiologicalDurvalumab
Given IV
Also known as: Imfinzi, Immunoglobulin G1, Anti-(Human Protein B7-H1) (Human Monoclonal MEDI4736 Heavy Chain), Disulfide with Human Monoclonal MEDI4736 Kappa-chain, Dimer, MEDI 4736, MEDI-4736, MEDI4736
RadiationIntensity-Modulated Radiation Therapy
Undergo IMRT
Also known as: IMRT, Intensity modulated radiation therapy (procedure), Intensity Modulated RT, Intensity-Modulated Radiotherapy, Radiation, Intensity-Modulated Radiotherapy
OtherLaboratory Biomarker Analysis
Correlative studies
OtherQuality-of-Life Assessment
Ancillary studies
Also known as: Quality of Life Assessment
OtherQuestionnaire Administration
Ancillary studies

What researchers measure

Primary outcomes

Number of Participants With Dose-limiting Toxicity (DLT) [Lead-in Phase]
DLTs were collected to verify the safety of durvalumab with RT in this population. Safety was determined if ≤ 2 of 8 participants in the cohort had any DLT, in which case the study would proceed to phase II with that dose schedule (DS). The probability for the DS to be deemed too toxic, given a true toxicity rate ≥ 45%, is at least 78%. With a true toxicity rate ≤ 20%, the probability for the DS do be deemed safe is 80%. The full DLT definition does not fit here, but includes all grade 5 AEs, grade 3 or 4 AEs definitely or probably related to durvalumab (DPRD) except for specified AEs and situations, and incomplete or \> 2-week delay completing RT due to immune toxicity DPRD. AEs were graded according to National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 4.0, which grade severity from 1=mild to 5=death. Two alternate DSs with a delayed 2nd dose (to reduce/avoid doses concurrent with RT) would be tried if the initial DS was too toxic.
Time frame: From start of durvalumab to 4 weeks after radiation therapy, approximately 13 weeks. Weekly during RT, at RT end, prior to adjuvant durvalumab, one month after end of RT.
Progression-free Survival (Percentage of Participants Alive Without Progression) [Phase II Primary]
Progression (failure) is defined as local, regional, or distant disease progression, or death from any cause. Progression was assessed by imaging, clinical assessment, or biopsy. Failure time is defined as time from randomization to failure or last follow-up (censored). Failure rates are estimated using the Kaplan-Meier method. The protocol specifies that the distributions of failure times be compared between the arms, which is reported in the statistical analysis results. Two-year estimates are provided. Analysis was planned to occur after 69 failure events had been reported.
Time frame: From randomization to last follow-up: weekly during RT, after end of RT: every 4 months for 1 year, every 6 months for 2 years, then annually. Additionally, every 4 weeks during adjuvant durvalumab. Maximum follow-up at time of analysis was 4.2 years.
Overall Survival (Percentage of Participants Alive) [Originally Phase III Primary / Now Phase II Secondary]
Overall survival (OS) time is defined as time from randomization to the date of death from any cause or last known follow-up (censored). Overall survival rates are estimated by the Kaplan-Meier method. The protocol specifies that the distributions of failure times be compared between the arms, which is reported in the statistical analysis results. Two-year estimates are provided.
Time frame: From randomization to last follow-up: weekly during RT, after end of RT: every 4 months for 1 year, every 6 months for 2 years, then annually. Additionally, every 4 weeks during adjuvant durvalumab. Maximum follow-up at time of analysis was 4.2 years.

Secondary outcomes

Locoregional Failure (Percentage of Participants With Locoregional Failure)
Locoregional progression is defined as local or regional progression or recurrence, death due to study cancer or unknown causes without documented progression. Progression was assessed by imaging, clinical assessment, or biopsy. Failure time is defined as time from randomization to failure, distant metastasis (competing risk), deaths from other causes (competing risk), or last follow-up (censored). Failure rates are estimated using the cumulative incidence method. The protocol specifies that the distributions of failure times be compared between the arms, which is reported in the statistical analysis results. Two-year estimates are provided.
Time frame: From randomization to last follow-up: weekly during RT, after end of RT: every 4 months for 1 year, every 6 months for 2 years, then annually. Additionally, every 4 weeks during adjuvant durvalumab. Maximum follow-up at time of analysis was 4.2 years.
Distant Metastasis (Percentage of Participants With Distant Metastasis)
Failure is defined as the occurrence of distant metastasis. Failure time is defined as time from randomization to first occurrence of distant metastasis, local or regional progression or recurrence (competing risk), death (competing risk), or last follow-up (censored). Failure rates are estimated using the cumulative incidence method. The protocol specifies that the distributions of failure times be compared between the arms, which is reported in the statistical analysis results. Two-year estimates are provided.
Time frame: From randomization to last follow-up: weekly during RT, after end of RT: every 4 months for 1 year, every 6 months for 2 years, then annually. Additionally, every 4 weeks during adjuvant durvalumab. Maximum follow-up at time of analysis was 4.2 years.
Competing Mortality (Percentage of Participants Who Died Due to Causes Other Than Study Cancer)
Failure is defined as Death from second primary, protocol treatment, or "other cause". Failure time is defined as time from randomization to first occurrence of failure, death due to study cancer or unknown cause (competing risk), or last follow-up (censored). Failure rates are estimated using the cumulative incidence method. The protocol specifies that the distributions of failure times be compared between the arms, which is reported in the statistical analysis results. Two-year estimates are provided.
Time frame: From randomization to last follow-up: weekly during RT, after end of RT: every 4 months for 1 year, every 6 months for 2 years, then annually. Additionally, every 4 weeks during adjuvant durvalumab. Maximum follow-up at time of analysis was 4.2 years.
Percentage of Participants With Complete or Partial Response at 4-month Scan Determined by Response Evaluation Criteria in Solid Tumors (RECIST) v. 1.1
Fludeoxyglucose F-18 positron emission tomography/computed tomography (FDG-PET/CT) scans at baseline and four months after the end of radiation therapy are compared. Per RECIST 1.1: * Complete response: * Disappearance of all lesions and pathologic lymph nodes * Partial response: * ≥ 30% decrease sum of the longest diameters * No new lesions * No progression of non-target lesions
Time frame: Baseline and 4 months after end of RT (approximately 6.5 months)
Number of Participants by Highest Grade Adverse Event Reported
Common Terminology Criteria for Adverse Events (version 5.0) grades adverse event severity from 1=mild to 5=death. Summary data is provided in this outcome measure; see Adverse Events Module for specific adverse event data.
Time frame: From randomization to last follow-up: weekly during RT, RT end, from end of RT: months 1, (Cetuximab: 2, 3,) 4, 8, 12, 18, 24, 30, 36, then annually. Additionally, prior to each adjuvant durvalumab cycle. Maximum follow-up at time of analysis= 4.2 yr.
Change in the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC QLQ C30) Physical Functioning Score at One Year
The EORTC QLQ C30 Physical Functioning score measures patient reported limitations in physical activities. Possible scores for each score range from 0 to 100, with higher scores indicating better physical functioning. Change is defined as the time point score minus the baseline score, where positive values indicate improvement for and negative values indicate.
Time frame: Baseline and one year after end of radiation therapy (approximately 7 weeks)
Change in MD Anderson Dysphagia Inventory (MDADI) Composite Score at One Year
The MDADI Composite score measures overall swallowing related quality of life derived from the emotional, functional, and physical scores, excluding the global item. Possible scores range from 20 to 100, with higher scores indicating better swallowing related quality of life. Change is defined as the time point score minus the baseline score, where positive values indicate improvement and negative values indicate decline.
Time frame: Baseline and one year after end of radiation therapy (approximately 7 weeks)
Change in Performance Status Scale for Head and Neck Cancer (PSS HN) Normalcy of Diet Score at One Year
The PSS HN Normalcy of Diet score measures clinician rated normalcy of diet. Possible scores range from 0 to 100, with higher scores indicating better dietary function. Change is defined as the time point score minus the baseline score, where positive values indicate improvement and negative values indicate worsening function.
Time frame: Baseline and one year after end of radiation therapy (approximately 7 weeks)
Change in PSS HN Eating in Public Score at One Year
The PSS HN Eating in Public score measures clinician rated public eating. Possible scores range from 0 to 100, with higher scores indicating better eating function. Change is defined as the time point score minus the baseline score, where positive values indicate improvement and negative values indicate worsening function.
Time frame: Baseline and one year after end of radiation therapy (approximately 7 weeks)
Change in PSS HN Understandability of Speech Score at One Year
The PSS HN Understandability of Speech score measures clinician rated speech. Possible scores range from 0 to 100, with higher scores indicating better speech function. Change is defined as the time point score minus the baseline score, where positive values indicate improvement and negative values indicate worsening function.
Time frame: Baseline and one year after end of radiation therapy (approximately 7 weeks)
Progression-free Survival (Percentage of Participants Alive Without Progression) by Baseline PD-L1 (Programmed Cell Death Ligand 1) Expression
Failure for progression-free survival is defined as local, regional, or distant disease progression, or death from any cause. Progression was assessed by imaging, clinical assessment, or biopsy. Failure time is defined as time from randomization to failure or last follow-up (censored). PD-L1 expression is defined by a combined positive score (CPS) ≥ 1, assessed by masked central analysis of baseline tissue specimens. CPS = \[(number of tumor cells positive for PD-L1) / (number of tumor cells positive for PD-L1 + number of tumor cells negative for PD-L1)\] multiplied by 100, yielding a possible score of 0 to 100. Treatment effect hazard ratios within PD-L1 subgroup were estimated by Cox proportional hazards model and progression-free survival estimates were estimated by Kaplan-Meier method. Analysis was planned to occur after 69 failure events had been reported and tissue specimen analysis was complete.
Time frame: From randomization to date of progression or last follow-up, whichever occurs first. Maximum follow-up at time of analysis was 4.2 years. Two-year PFS estimates are reported.
Progression-free Survival (Percentage of Participants Alive Without Progression) by Baseline p16 Status
Failure for progression-free survival is defined as local, regional, or distant disease progression, or death from any cause. Progression was assessed by imaging, clinical assessment, or biopsy. Failure time is defined as time from randomization to failure or last follow-up (censored). Positive p16 status was defined as more than 70% strong nuclear or nuclear and cytoplasmic staining of tumor cells, confirmed by central pathology review. Treatment effect hazard ratios within p16 subgroup were estimated by Cox proportional hazards model and progression-free survival estimates were estimated by Kaplan-Meier method. Analysis was planned to occur after 69 failure events had been reported and tissue specimen analysis was complete.
Time frame: From randomization to date of progression or last follow-up, whichever occurs first. Maximum follow-up at time of analysis was 4.2 years. Two-year PFS estimates are reported.

Other outcomes

Change in the EORTC QLQ C30 Global Heath Status Score at One Year
The EORTC QLQ C30 Global Heath Status score measures overall health related quality of life. Possible scores for each scale range from 0 to 100, with higher scores indicate better overall quality of life. Change is defined as the time point score minus the baseline score, where positive values indicate improvement for and negative values indicate.
Time frame: Baseline and one year
Change in the EORTC QLQ C30 Fatigue Score at One Year
The EORTC QLQ C30 fatigue score measures patient reported fatigue symptom burden. Possible scores for each score range from 0 to 100, with higher scores indicating worse fatigue. Change is defined as the time point score minus the baseline score, where negative values indicate improvement for and positive values indicate.
Time frame: Baseline and one year
Change in EORTC QLQ-C30 H&N35 Swallowing Score at One Year
The EORTC QLQ-H\&N35 swallowing score measures patient-reported difficulty with swallowing various foods and liquid and ranges from 0 (no swallowing problems) to 100 (maximum swallowing difficulty). A positive change from baseline indicates worsening swallowing function.
Time frame: Baseline and one year
Change in MDADI Global Score at One Year
The MDADI Global score measures patient reported overall swallowing related quality of life. Possible scores range from 20 to 100, with higher scores indicating better swallowing related quality of life. Change is defined as the time point score minus the baseline score, where positive values indicate improvement and negative values indicate decline.
Time frame: Baseline and one year
Change in MDADI Emotional Score at One Year
The MDADI Emotional score measures the emotional impact of swallowing difficulties on quality of life. Possible scores range from 20 to 100, with higher scores indicating better swallowing related quality of life. Change is defined as the time point score minus the baseline score, where positive values indicate improvement and negative values indicate decline.
Time frame: Baseline and one year
Change in MDADI Functional Score at One Year
The MDADI Functional score measures the functional impact of swallowing difficulties on daily activities. Possible scores range from 20 to 100, with higher scores indicating better swallowing related quality of life. Change is defined as the time point score minus the baseline score, where positive values indicate improvement and negative values indicate decline.
Time frame: Baseline and one year
Change in MDADI Physical Score at One Year
The MDADI Physical score measures the physical aspects of swallowing difficulties and their impact on swallowing related quality of life. Possible scores range from 20 to 100, with higher scores indicating better swallowing related quality of life. Change is defined as the time point score minus the baseline score, where positive values indicate improvement and negative values indicate decline.
Time frame: Baseline and one year
Change in EuroQol 5 Dimension 5 Level (EQ 5D 5L) Index Score at One Year
The EQ-5D-5L Index score measures health related quality of life based on responses to five dimensions: mobility, self care, usual activities, pain/discomfort, and anxiety/depression. Possible scores range from 0 (worst health state) to 1(best health state). Change is defined as the time point score minus the baseline score, where positive values indicate improvement and negative values indicate decline.
Time frame: Baseline and 1 year
Change in EQ 5D 5L Visual Analogue Scale at One Year
The EQ 5D 5L Visual Analogue Scale measures self rated overall health on a vertical visual analogue scale. Possible scores range from 0 for the worst imaginable health state) to 100 for the best imaginable health state. Change is defined as the time point score minus the baseline score, where positive values indicate improvement and negative values indicate decline.
Time frame: Baseline and 1 year
Secondary Biomarker Analysis
Will perform multiparametric flow cytometry on peripheral mononuclear cells (PBMC) from patient-derived blood samples to quantify changes in immune cell frequency and activation status before, during and after radiation combined with cetuximab or radiation combined with durvalumab. To assess the statistical significance of pre- to post-treatment changes in levels of immunoglobulin (Ig)Gs as well as other markers, normalized signal intensities (log2) will be tested using a paired t test within an arm and two sample t test between the two arms. If the distribution assumption is violated for the t tests, nonparametric tests, such as the Wilcoxon signed-rank test will be considered. Lastly, the association between PFS and OS and post-treatment changes in frequency and activation state of T-cells, clonality and diversity of T cell receptor (TCR), and IgG levels will be evaluated using a two-sided Wald test at 0.05 level on the basis of Cox models.
Time frame: Baseline up to 4 months after RT
Patient Reported Outcomes-Common Terminology Criteria for Adverse Events (PRO-CTCAE)
PRO-CTCAE is not intended for expedited reporting, real time review or safety reporting. PRO-CTCAE data are exploratory and not currently intended for use in data safety monitoring or adverse event stopping rules.
Time frame: Up to 3 years
QOL Endpoints Using Other Items in EORTC QLQ/HN35, EQ5D and MDADI Subscales
The mean change from baseline at each time point will be summarized using mean and standard deviations for each arm. Mean change from baseline will be compared between the arms using a two sample t test. If data normality assumptions are not met, the Wilcoxon rank sum test will be used to test the hypothesis. Mean change from baseline will be tested using an omnibus F test followed by individual comparisons of change scores at different time points within each treatment group. The same analysis will be conducted for between group comparisons at each time point.
Time frame: Up to 12-24 months from end of RT

Results

Posted Oct 25, 2023

Limitations and caveats

Phase II (phII) component stopped enrollment early due to toxicity and futility concerns, with 186 of the 234 planned participants, but continued to collect data required for the final phII analysis. Per the protocol, the study did not continue to phase III (phIII). Therefore, the phIII primary outcome measure (OM) of overall survival was analyzed as a phII secondary OM. Accordingly, the phIII PD-L1 and p16 analyses were analyzed using the phII primary OM of progression-free survival.

Participant flow

Lead-in Component

Participant flow — Lead-in Component
Milestone	(Lead-in) RT + Durvalumab	RT + Cetuximab	RT + Durvalumab
Started	10	0	0
Started treatment	10	0	0
Completed	10	0	0
Not completed	0	0	0

Randomized Component

Participant flow — Randomized Component
Milestone	RT + Cetuximab	RT + Durvalumab
Started	63	123
Started treatment	61	119
Completed	63	123
Not completed	0	0

Outcome measures

PrimaryNumber of Participants With Dose-limiting Toxicity (DLT) [Lead-in Phase]

DLTs were collected to verify the safety of durvalumab with RT in this population. Safety was determined if ≤ 2 of 8 participants in the cohort had any DLT, in which case the study would proceed to phase II with that dose schedule (DS). The probability for the DS to be deemed too toxic, given a true toxicity rate ≥ 45%, is at least 78%. With a true toxicity rate ≤ 20%, the probability for the DS do be deemed safe is 80%. The full DLT definition does not fit here, but includes all grade 5 AEs, grade 3 or 4 AEs definitely or probably related to durvalumab (DPRD) except for specified AEs and situations, and incomplete or \> 2-week delay completing RT due to immune toxicity DPRD. AEs were graded according to National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 4.0, which grade severity from 1=mild to 5=death. Two alternate DSs with a delayed 2nd dose (to reduce/avoid doses concurrent with RT) would be tried if the initial DS was too toxic.

Time frame:: From start of durvalumab to 4 weeks after radiation therapy, approximately 13 weeks. Weekly during RT, at RT end, prior to adjuvant durvalumab, one month after end of RT.
Reported as:: Count of participants · Participants

Number of Participants With Dose-limiting Toxicity (DLT) [Lead-in Phase]
Participants	(Lead-in) RT + Durvalumab
Number of Participants With Dose-limiting Toxicity (DLT) [Lead-in Phase]	0

PrimaryProgression-free Survival (Percentage of Participants Alive Without Progression) [Phase II Primary]

Progression (failure) is defined as local, regional, or distant disease progression, or death from any cause. Progression was assessed by imaging, clinical assessment, or biopsy. Failure time is defined as time from randomization to failure or last follow-up (censored). Failure rates are estimated using the Kaplan-Meier method. The protocol specifies that the distributions of failure times be compared between the arms, which is reported in the statistical analysis results. Two-year estimates are provided. Analysis was planned to occur after 69 failure events had been reported.

Time frame:: From randomization to last follow-up: weekly during RT, after end of RT: every 4 months for 1 year, every 6 months for 2 years, then annually. Additionally, every 4 weeks during adjuvant durvalumab. Maximum follow-up at time of analysis was 4.2 years.
Reported as:: Number · percentage of participants

Progression-free Survival (Percentage of Participants Alive Without Progression) [Phase II Primary]
percentage of participants	RT + Cetuximab	RT + Durvalumab
Progression-free Survival (Percentage of Participants Alive Without Progression) [Phase II Primary]	63.7 (51.3 to 76.1)	50.6 (41.5 to 59.8)

Statistical analysis

RT + Cetuximab vs RT + Durvalumab · Log Rank · p = 0.8878 (One-sided significance level = 0.2) · Hazard ratio (hr): 1.33 · 95% CI 0.84 to 2.12Reference arm = radiation therapy + cetuximab

PrimaryOverall Survival (Percentage of Participants Alive) [Originally Phase III Primary / Now Phase II Secondary]

Overall survival (OS) time is defined as time from randomization to the date of death from any cause or last known follow-up (censored). Overall survival rates are estimated by the Kaplan-Meier method. The protocol specifies that the distributions of failure times be compared between the arms, which is reported in the statistical analysis results. Two-year estimates are provided.

Time frame:: From randomization to last follow-up: weekly during RT, after end of RT: every 4 months for 1 year, every 6 months for 2 years, then annually. Additionally, every 4 weeks during adjuvant durvalumab. Maximum follow-up at time of analysis was 4.2 years.
Reported as:: Number · percentage of participants

Overall Survival (Percentage of Participants Alive) [Originally Phase III Primary / Now Phase II Secondary]
percentage of participants	RT+ Cetuximab	RT + Durvalumab
Overall Survival (Percentage of Participants Alive) [Originally Phase III Primary / Now Phase II Secondary]	77.5 (66.7 to 88.3)	69.3 (60.8 to 77.8)

Statistical analysis

RT+ Cetuximab vs RT + Durvalumab · Log Rank · p = 0.8175 (One-side significance level = 0.025) · Hazard ratio (hr): 1.30 · 95% CI 0.74 to 2.28

SecondaryLocoregional Failure (Percentage of Participants With Locoregional Failure)

Locoregional progression is defined as local or regional progression or recurrence, death due to study cancer or unknown causes without documented progression. Progression was assessed by imaging, clinical assessment, or biopsy. Failure time is defined as time from randomization to failure, distant metastasis (competing risk), deaths from other causes (competing risk), or last follow-up (censored). Failure rates are estimated using the cumulative incidence method. The protocol specifies that the distributions of failure times be compared between the arms, which is reported in the statistical analysis results. Two-year estimates are provided.

Time frame:: From randomization to last follow-up: weekly during RT, after end of RT: every 4 months for 1 year, every 6 months for 2 years, then annually. Additionally, every 4 weeks during adjuvant durvalumab. Maximum follow-up at time of analysis was 4.2 years.
Reported as:: Number · percentage of participants

Locoregional Failure (Percentage of Participants With Locoregional Failure)
percentage of participants	RT+ Cetuximab	RT + Durvalumab
Locoregional Failure (Percentage of Participants With Locoregional Failure)	18.9 (10.0 to 29.9)	31.3 (23.0 to 40.0)

Statistical analysis

RT+ Cetuximab vs RT + Durvalumab · Log Rank · p = 0.1001 (Two-sided significance level = 0.05) · Hazard ratio (hr): 1.71 · 95% CI 0.89 to 3.28Reference level = RT+ Cetuximab

SecondaryDistant Metastasis (Percentage of Participants With Distant Metastasis)

Failure is defined as the occurrence of distant metastasis. Failure time is defined as time from randomization to first occurrence of distant metastasis, local or regional progression or recurrence (competing risk), death (competing risk), or last follow-up (censored). Failure rates are estimated using the cumulative incidence method. The protocol specifies that the distributions of failure times be compared between the arms, which is reported in the statistical analysis results. Two-year estimates are provided.

Time frame:: From randomization to last follow-up: weekly during RT, after end of RT: every 4 months for 1 year, every 6 months for 2 years, then annually. Additionally, every 4 weeks during adjuvant durvalumab. Maximum follow-up at time of analysis was 4.2 years.
Reported as:: Number · percentage of participants

Distant Metastasis (Percentage of Participants With Distant Metastasis)
percentage of participants	RT+ Cetuximab	RT + Durvalumab
Distant Metastasis (Percentage of Participants With Distant Metastasis)	12.1 (5.3 to 22.0)	9.5 (5.0 to 15.7)

Statistical analysis

RT+ Cetuximab vs RT + Durvalumab · Log Rank · p = 0.5197 (Two-sided significance level = 0.05) · Hazard ratio (hr): 0.76 · 95% CI 0.32 to 1.77Reference level = RT+ Cetuximab

SecondaryCompeting Mortality (Percentage of Participants Who Died Due to Causes Other Than Study Cancer)

Failure is defined as Death from second primary, protocol treatment, or "other cause". Failure time is defined as time from randomization to first occurrence of failure, death due to study cancer or unknown cause (competing risk), or last follow-up (censored). Failure rates are estimated using the cumulative incidence method. The protocol specifies that the distributions of failure times be compared between the arms, which is reported in the statistical analysis results. Two-year estimates are provided.

Time frame:: From randomization to last follow-up: weekly during RT, after end of RT: every 4 months for 1 year, every 6 months for 2 years, then annually. Additionally, every 4 weeks during adjuvant durvalumab. Maximum follow-up at time of analysis was 4.2 years.
Reported as:: Number · percentage of participants

Competing Mortality (Percentage of Participants Who Died Due to Causes Other Than Study Cancer)
percentage of participants	RT+ Cetuximab	RT + Durvalumab
Competing Mortality (Percentage of Participants Who Died Due to Causes Other Than Study Cancer)	5.3 (1.4 to 13.4)	10.5 (5.7 to 17.0)

Statistical analysis

RT+ Cetuximab vs RT + Durvalumab · Log Rank · p = 0.3201 (Two-sided significance level = 0.05) · Hazard ratio (hr): 1.75 · 95% CI 0.57 to 5.38

SecondaryPercentage of Participants With Complete or Partial Response at 4-month Scan Determined by Response Evaluation Criteria in Solid Tumors (RECIST) v. 1.1

Fludeoxyglucose F-18 positron emission tomography/computed tomography (FDG-PET/CT) scans at baseline and four months after the end of radiation therapy are compared. Per RECIST 1.1: * Complete response: * Disappearance of all lesions and pathologic lymph nodes * Partial response: * ≥ 30% decrease sum of the longest diameters * No new lesions * No progression of non-target lesions

Time frame:: Baseline and 4 months after end of RT (approximately 6.5 months)
Reported as:: Number · percentage of participants

Percentage of Participants With Complete or Partial Response at 4-month Scan Determined by Response Evaluation Criteria in Solid Tumors (RECIST) v. 1.1
percentage of participants	RT+ Cetuximab	RT + Durvalumab
Percentage of Participants With Complete or Partial Response at 4-month Scan Determined by Response Evaluation Criteria in Solid Tumors (RECIST) v. 1.1	72.7 (51.8 to 86.8)	75.9 (57.9 to 87.8)

Statistical analysis

RT+ Cetuximab vs RT + Durvalumab · Fisher Exact · p = 1.00 (Two-sided significance level = 0.05)

SecondaryNumber of Participants by Highest Grade Adverse Event Reported

Common Terminology Criteria for Adverse Events (version 5.0) grades adverse event severity from 1=mild to 5=death. Summary data is provided in this outcome measure; see Adverse Events Module for specific adverse event data.

Time frame:: From randomization to last follow-up: weekly during RT, RT end, from end of RT: months 1, (Cetuximab: 2, 3,) 4, 8, 12, 18, 24, 30, 36, then annually. Additionally, prior to each adjuvant durvalumab cycle. Maximum follow-up at time of analysis= 4.2 yr.
Reported as:: Count of participants · Participants

Number of Participants by Highest Grade Adverse Event Reported
Participants	RT+ Cetuximab	RT + Durvalumab
< Grade 3	12	36
Grade 3	37	57
Grade 4	11	15
Grade 5	1	11

Statistical analysis

RT+ Cetuximab vs RT + Durvalumab · Fisher Exact · p = 0.0688 (Two-side significance level = 0.05)

SecondaryChange in the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC QLQ C30) Physical Functioning Score at One Year

The EORTC QLQ C30 Physical Functioning score measures patient reported limitations in physical activities. Possible scores for each score range from 0 to 100, with higher scores indicating better physical functioning. Change is defined as the time point score minus the baseline score, where positive values indicate improvement for and negative values indicate.

Time frame:: Baseline and one year after end of radiation therapy (approximately 7 weeks)
Reported as:: Mean · score on a scale

Change in the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC QLQ C30) Physical Functioning Score at One Year
score on a scale	RT+ Cetuximab	RT + Durvalumab
Change in the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC QLQ C30) Physical Functioning Score at One Year	-1.90 (-12.24 to 8.43)	-1.49 (-6.23 to 3.24)

Statistical analysis

RT+ Cetuximab vs RT + Durvalumab · t-test, 2 sided · p = 0.9416 (Two-sided significance level = 0.05)Welch t-test (unequal variances)

SecondaryChange in MD Anderson Dysphagia Inventory (MDADI) Composite Score at One Year

The MDADI Composite score measures overall swallowing related quality of life derived from the emotional, functional, and physical scores, excluding the global item. Possible scores range from 20 to 100, with higher scores indicating better swallowing related quality of life. Change is defined as the time point score minus the baseline score, where positive values indicate improvement and negative values indicate decline.

Time frame:: Baseline and one year after end of radiation therapy (approximately 7 weeks)
Reported as:: Mean · score on a scale

Change in MD Anderson Dysphagia Inventory (MDADI) Composite Score at One Year
score on a scale	RT + Cetuximab	RT + Durvalumab
Change in MD Anderson Dysphagia Inventory (MDADI) Composite Score at One Year	-0.62 (-5.91 to 4.66)	-3.48 (-8.05 to 1.09)

Statistical analysis

RT + Cetuximab vs RT + Durvalumab · t-test, 2 sided · p = 0.4085 (Two-sided significance level = 0.05)Welch t-test (unequal variances)

SecondaryChange in Performance Status Scale for Head and Neck Cancer (PSS HN) Normalcy of Diet Score at One Year

The PSS HN Normalcy of Diet score measures clinician rated normalcy of diet. Possible scores range from 0 to 100, with higher scores indicating better dietary function. Change is defined as the time point score minus the baseline score, where positive values indicate improvement and negative values indicate worsening function.

Time frame:: Baseline and one year after end of radiation therapy (approximately 7 weeks)
Reported as:: Mean · score on a scale

Change in Performance Status Scale for Head and Neck Cancer (PSS HN) Normalcy of Diet Score at One Year
score on a scale	RT + Cetuximab	RT + Durvalumab
Change in Performance Status Scale for Head and Neck Cancer (PSS HN) Normalcy of Diet Score at One Year	-2.27 (-14.66 to 10.11)	-6.47 (-15.05 to 2.11)

Statistical analysis

RT + Cetuximab vs RT + Durvalumab · t-test, 2 sided · p = 0.5698 (Two-sided significance level = 0.05)Welch t-test (unequal variances)

SecondaryChange in PSS HN Eating in Public Score at One Year

The PSS HN Eating in Public score measures clinician rated public eating. Possible scores range from 0 to 100, with higher scores indicating better eating function. Change is defined as the time point score minus the baseline score, where positive values indicate improvement and negative values indicate worsening function.

Time frame:: Baseline and one year after end of radiation therapy (approximately 7 weeks)
Reported as:: Mean · score on a scale

Change in PSS HN Eating in Public Score at One Year
score on a scale	RT + Cetuximab	RT + Durvalumab
Change in PSS HN Eating in Public Score at One Year	-11.36 (-24.04 to 1.31)	-8.82 (-17.47 to -0.17)

Statistical analysis

RT + Cetuximab vs RT + Durvalumab · t-test, 2 sided · p = 0.7352 (Two-sided significance level = 0.05)Welch t-test (unequal variances)

SecondaryChange in PSS HN Understandability of Speech Score at One Year

The PSS HN Understandability of Speech score measures clinician rated speech. Possible scores range from 0 to 100, with higher scores indicating better speech function. Change is defined as the time point score minus the baseline score, where positive values indicate improvement and negative values indicate worsening function.

Time frame:: Baseline and one year after end of radiation therapy (approximately 7 weeks)
Reported as:: Mean · score on a scale

Change in PSS HN Understandability of Speech Score at One Year
score on a scale	RT + Cetuximab	RT + Durvalumab
Change in PSS HN Understandability of Speech Score at One Year	-3.41 (-9.62 to 2.80)	-8.82 (-16.11 to -1.54)

Statistical analysis

RT + Cetuximab vs RT + Durvalumab · t-test, 2 sided · p = 0.2531 (Two-sided significance level = 0.05)Welch t-test (unequal variances)

SecondaryProgression-free Survival (Percentage of Participants Alive Without Progression) by Baseline PD-L1 (Programmed Cell Death Ligand 1) Expression

Failure for progression-free survival is defined as local, regional, or distant disease progression, or death from any cause. Progression was assessed by imaging, clinical assessment, or biopsy. Failure time is defined as time from randomization to failure or last follow-up (censored). PD-L1 expression is defined by a combined positive score (CPS) ≥ 1, assessed by masked central analysis of baseline tissue specimens. CPS = \[(number of tumor cells positive for PD-L1) / (number of tumor cells positive for PD-L1 + number of tumor cells negative for PD-L1)\] multiplied by 100, yielding a possible score of 0 to 100. Treatment effect hazard ratios within PD-L1 subgroup were estimated by Cox proportional hazards model and progression-free survival estimates were estimated by Kaplan-Meier method. Analysis was planned to occur after 69 failure events had been reported and tissue specimen analysis was complete.

Time frame:: From randomization to date of progression or last follow-up, whichever occurs first. Maximum follow-up at time of analysis was 4.2 years. Two-year PFS estimates are reported.
Reported as:: Number · percentage of participants

Progression-free Survival (Percentage of Participants Alive Without Progression) by Baseline PD-L1 (Programmed Cell Death Ligand 1) Expression
percentage of participants	RT + Cetuximab	RT + Durvalumab
CPS ≥ 1 (PD-L1 expression)	59.9 (43.6 to 76.2)	54.8 (43.9 to 65.6)
CPS = 0 (no PD-L1 expression)	61.5 (35.1 to 88.0)	30.0 (9.9 to 50.1)

Statistical analysis

RT + Cetuximab vs RT + Durvalumab · Cox proportional hazard: 1.11 · 95% CI 0.62 to 1.97Reference arm = RT + Cetuximab
RT + Cetuximab vs RT + Durvalumab · Cox proportional hazard: 1.64 · 95% CI 0.66 to 4.06Reference arm = RT + Cetuximab
RT + Cetuximab vs RT + Durvalumab · Regression, Cox · p = 0.41 (Testing the interaction of treatment arm and PD-L1 expression (CPS ≥ 1, CPS = 0))

SecondaryProgression-free Survival (Percentage of Participants Alive Without Progression) by Baseline p16 Status

Failure for progression-free survival is defined as local, regional, or distant disease progression, or death from any cause. Progression was assessed by imaging, clinical assessment, or biopsy. Failure time is defined as time from randomization to failure or last follow-up (censored). Positive p16 status was defined as more than 70% strong nuclear or nuclear and cytoplasmic staining of tumor cells, confirmed by central pathology review. Treatment effect hazard ratios within p16 subgroup were estimated by Cox proportional hazards model and progression-free survival estimates were estimated by Kaplan-Meier method. Analysis was planned to occur after 69 failure events had been reported and tissue specimen analysis was complete.

Time frame:: From randomization to date of progression or last follow-up, whichever occurs first. Maximum follow-up at time of analysis was 4.2 years. Two-year PFS estimates are reported.
Reported as:: Number · percentage of participants

Progression-free Survival (Percentage of Participants Alive Without Progression) by Baseline p16 Status
percentage of participants	RT + Cetuximab	RT + Durvalumab
p16-positive	74.8 (59.6 to 89.9)	68.8 (57.4 to 80.1)
p16-negative	48.1 (27.6 to 68.5)	23.2 (10.1 to 36.3)

Statistical analysis

RT + Cetuximab vs RT + Durvalumab · Hazard ratio (hr): 1.20 · 95% CI 0.57 to 2.51Reference arm = RT + cetuximab
RT + Cetuximab vs RT + Durvalumab · Hazard ratio (hr): 1.55 · 95% CI 0.83 to 2.89Reference arm = RT + cetuximab
RT + Cetuximab vs RT + Durvalumab · Regression, Cox · p = 0.61 (Testing the interaction of treatment arm and p16 status (positive, negative))

Other pre-specifiedChange in the EORTC QLQ C30 Global Heath Status Score at One Year

The EORTC QLQ C30 Global Heath Status score measures overall health related quality of life. Possible scores for each scale range from 0 to 100, with higher scores indicate better overall quality of life. Change is defined as the time point score minus the baseline score, where positive values indicate improvement for and negative values indicate.

Time frame:: Baseline and one year