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
Conditions
Brief 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.
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.
Interventions
Given IV
Given IV
Undergo IMRT
Correlative studies
Ancillary studies
Ancillary studies
Sponsors
Study design
Eligibility
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
* PRIOR TO STEP 1 REGISTRATION
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Overall Survival (Percentage of Participants Alive) [Originally Phase III Primary / Now Phase II Secondary] | 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 (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. |
| Number of Participants With Dose-limiting Toxicity (DLT) [Lead-in Phase] | 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. | 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. |
| Progression-free Survival (Percentage of Participants Alive Without Progression) [Phase II Primary] | 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. | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Competing Mortality (Percentage of Participants Who Died Due to Causes Other Than Study Cancer) | 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. | 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. |
| Percentage of Participants With Complete or Partial Response at 4-month Scan Determined by Response Evaluation Criteria in Solid Tumors (RECIST) v. 1.1 | Baseline and 4 months after end of RT (approximately 6.5 months) | 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 |
| Number of Participants by Highest Grade Adverse Event Reported | 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. | 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. |
| 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 | Baseline and one year after end of radiation therapy (approximately 7 weeks) | 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. |
| Change in Performance Status Scale for Head and Neck Cancer (PSS HN) Normalcy of Diet Score at One Year | Baseline and one year after end of radiation therapy (approximately 7 weeks) | 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. |
| Change in PSS HN Eating in Public Score at One Year | Baseline and one year after end of radiation therapy (approximately 7 weeks) | 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. |
| Change in PSS HN Understandability of Speech Score at One Year | Baseline and one year after end of radiation therapy (approximately 7 weeks) | 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. |
| Progression-free Survival (Percentage of Participants Alive Without Progression) by Baseline PD-L1 (Programmed Cell Death Ligand 1) Expression | 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. | 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. |
| Change in MD Anderson Dysphagia Inventory (MDADI) Composite Score at One Year | Baseline and one year after end of radiation therapy (approximately 7 weeks) | 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. |
| Progression-free Survival (Percentage of Participants Alive Without Progression) by Baseline p16 Status | 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. | 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. |
| Locoregional Failure (Percentage of Participants With Locoregional Failure) | 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. | 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. |
| Distant Metastasis (Percentage of Participants With Distant Metastasis) | 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. | 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. |
Countries
Canada, United States
Contacts
NRG Oncology
Participant flow
Pre-assignment details
Participants were first registered for screening. Central pathology review confirmation of p16 determination was an enrollment requirement for participants with oropharyngeal or unknown primary tumors. Overall,196 of 200 screened participants were enrolled.
Participants by arm
| Arm | Count |
|---|---|
| (Lead-in) RT + Durvalumab IMRT for seven weeks, 5 fractions/week. Durvalumab 1500 mg IV starts two weeks prior to RT and continues every 4 weeks for a total of seven cycles in the absence of disease progression or unacceptable toxicity. | 10 |
| RT + Cetuximab IMRT for seven weeks, 5 fractions/week. Cetuximab 400 mg/m\^2 IV starts one week prior to RT, then 250 mg/m\^2 weekly for seven additional cycles in the absence of disease progression or unacceptable toxicity. | 63 |
| RT + Durvalumab IMRT for seven weeks, 5 fractions/week. Durvalumab 1500 mg IV starts two weeks prior to RT and continues every 4 weeks for a total of seven cycles in the absence of disease progression or unacceptable toxicity. | 123 |
| Total | 196 |
Baseline characteristics
| Characteristic | RT + Durvalumab | (Lead-in) RT + Durvalumab | Total | RT + Cetuximab |
|---|---|---|---|---|
| Age, Customized ≤ 49 years | 2 Participants | 1 Participants | 4 Participants | 1 Participants |
| Age, Customized 50 - 59 years | 10 Participants | 0 Participants | 19 Participants | 9 Participants |
| Age, Customized 60 - 69 years | 35 Participants | 6 Participants | 61 Participants | 20 Participants |
| Age, Customized 70 - 79 years | 60 Participants | 3 Participants | 88 Participants | 25 Participants |
| Age, Customized ≥ 80 years | 16 Participants | 0 Participants | 24 Participants | 8 Participants |
| Comorbidity group Absolute or relative contraindication to cisplatin | 104 Participants | 6 Participants | 162 Participants | 52 Participants |
| Comorbidity group Age ≥ 70 with moderate to severe comorbidity or vulnerability to cisplatin | 12 Participants | 1 Participants | 17 Participants | 4 Participants |
| Comorbidity group Age < 70 with severe comorbidity or vulnerability to cisplatin | 7 Participants | 3 Participants | 17 Participants | 7 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 1 Participants | 10 Participants | 14 Participants | 3 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 117 Participants | 0 Participants | 173 Participants | 56 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 5 Participants | 0 Participants | 9 Participants | 4 Participants |
| Modified Charlson Comorbidity Index (CCI) 0 (no comorbidities) | 43 Participants | 4 Participants | 71 Participants | 24 Participants |
| Modified Charlson Comorbidity Index (CCI) ≥ 1 | 80 Participants | 6 Participants | 125 Participants | 39 Participants |
| N stage, clinical (AJCC 8) N0 | 17 Participants | 0 Participants | 31 Participants | 14 Participants |
| N stage, clinical (AJCC 8) N1 | 36 Participants | 2 Participants | 66 Participants | 28 Participants |
| N stage, clinical (AJCC 8) N2 | 21 Participants | 0 Participants | 29 Participants | 8 Participants |
| N stage, clinical (AJCC 8) N2a | 2 Participants | 0 Participants | 2 Participants | 0 Participants |
| N stage, clinical (AJCC 8) N2b | 21 Participants | 4 Participants | 28 Participants | 3 Participants |
| N stage, clinical (AJCC 8) N2c | 17 Participants | 4 Participants | 30 Participants | 9 Participants |
| N stage, clinical (AJCC 8) N3 | 4 Participants | 0 Participants | 4 Participants | 0 Participants |
| N stage, clinical (AJCC 8) N3a | 2 Participants | 0 Participants | 2 Participants | 0 Participants |
| N stage, clinical (AJCC 8) N3b | 3 Participants | 0 Participants | 4 Participants | 1 Participants |
| Number of comorbidity conditions 1 | 1 Participants | 0 Participants | 1 Participants | 0 Participants |
| Number of comorbidity conditions 2 | 5 Participants | 1 Participants | 9 Participants | 3 Participants |
| Number of comorbidity conditions 3 | 10 Participants | 3 Participants | 20 Participants | 7 Participants |
| Number of comorbidity conditions 4 | 23 Participants | 0 Participants | 37 Participants | 14 Participants |
| Number of comorbidity conditions 5 | 31 Participants | 2 Participants | 50 Participants | 17 Participants |
| Number of comorbidity conditions ≥ 6 | 53 Participants | 4 Participants | 79 Participants | 22 Participants |
| Primary tumor site and p16 status Hypopharynx | 13 Participants | 0 Participants | 21 Participants | 8 Participants |
| Primary tumor site and p16 status Larynx | 30 Participants | 2 Participants | 50 Participants | 18 Participants |
| Primary tumor site and p16 status Oral cavity | 6 Participants | 0 Participants | 10 Participants | 4 Participants |
| Primary tumor site and p16 status Oropharynx, p16-negative | 15 Participants | 2 Participants | 20 Participants | 3 Participants |
| Primary tumor site and p16 status Oropharynx, p16-positive | 55 Participants | 6 Participants | 88 Participants | 27 Participants |
| Primary tumor site and p16 status Unknown, p16-negative | 1 Participants | 0 Participants | 1 Participants | 0 Participants |
| Primary tumor site and p16 status Unknown, p16-positive | 3 Participants | 0 Participants | 6 Participants | 3 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 1 Participants | 0 Participants | 2 Participants | 1 Participants |
| Race (NIH/OMB) Asian | 2 Participants | 0 Participants | 3 Participants | 1 Participants |
| Race (NIH/OMB) Black or African American | 11 Participants | 0 Participants | 17 Participants | 6 Participants |
| Race (NIH/OMB) More than one race | 1 Participants | 0 Participants | 1 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 3 Participants | 0 Participants | 7 Participants | 4 Participants |
| Race (NIH/OMB) White | 105 Participants | 10 Participants | 165 Participants | 50 Participants |
| Sex: Female, Male Female | 21 Participants | 1 Participants | 31 Participants | 9 Participants |
| Sex: Female, Male Male | 102 Participants | 9 Participants | 165 Participants | 54 Participants |
| Smoking history: pack-years ≤ 10 pack-years | 35 Participants | 4 Participants | 60 Participants | 21 Participants |
| Smoking history: pack-years > 10 pack-years | 88 Participants | 6 Participants | 136 Participants | 42 Participants |
| Stratification factor: primary site and p16 status p16-negative oropharynx or unknown primary, larynx, hypopharynx or oral cavity | 65 Participants | NA Participants | NA Participants | 33 Participants |
| Stratification factor: primary site and p16 status p16-positive oropharynx or unknown primary | 58 Participants | NA Participants | NA Participants | 30 Participants |
| Stratification factor: T and N stage T0-3 and N0-2 | 88 Participants | NA Participants | NA Participants | 45 Participants |
| Stratification factor: T and N stage T4 and/or N3 | 35 Participants | NA Participants | NA Participants | 18 Participants |
| Stratification factor: Zubrod and modified CCI Zubrod 0 and modified CCI 0 | 20 Participants | NA Participants | NA Participants | 13 Participants |
| Stratification factor: Zubrod and modified CCI Zubrod 1-2 and/or modified CCI > 0 | 103 Participants | NA Participants | NA Participants | 50 Participants |
| T stage, clinical (AJCC 8) T0 | 4 Participants | 0 Participants | 7 Participants | 3 Participants |
| T stage, clinical (AJCC 8) T1 | 11 Participants | 3 Participants | 21 Participants | 7 Participants |
| T stage, clinical (AJCC 8) T2 | 38 Participants | 2 Participants | 56 Participants | 16 Participants |
| T stage, clinical (AJCC 8) T3 | 42 Participants | 3 Participants | 65 Participants | 20 Participants |
| T stage, clinical (AJCC 8) T4 | 15 Participants | 2 Participants | 28 Participants | 11 Participants |
| T stage, clinical (AJCC 8) T4a | 11 Participants | 0 Participants | 17 Participants | 6 Participants |
| T stage, clinical (AJCC 8) T4b | 2 Participants | 0 Participants | 2 Participants | 0 Participants |
| Zubrod performance status 0 | 48 Participants | 4 Participants | 80 Participants | 28 Participants |
| Zubrod performance status 1 | 60 Participants | 6 Participants | 93 Participants | 27 Participants |
| Zubrod performance status 2 | 15 Participants | 0 Participants | 23 Participants | 8 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 3 / 10 | 17 / 63 | 41 / 123 |
| other Total, other adverse events | 10 / 10 | 61 / 61 | 118 / 119 |
| serious Total, serious adverse events | 4 / 10 | 51 / 61 | 84 / 119 |
Outcome results
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.
Population: The first eight DLT evaluable participants in a given dose schedule cohort. An evaluable participant is defined as a participant who either (1) experienced a DLT and received at least one dose of durvalumab, or (2) received at least one dose of durvalumab and one fraction of radiation therapy (RT) and completed the DLT observation period (4 weeks after RT).
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| (Lead-in) RT + Durvalumab | Number of Participants With Dose-limiting Toxicity (DLT) [Lead-in Phase] | 0 Participants |
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.
Population: Randomized participants
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| (Lead-in) RT + Durvalumab | Overall Survival (Percentage of Participants Alive) [Originally Phase III Primary / Now Phase II Secondary] | 77.5 percentage of participants |
| RT + Durvalumab | Overall Survival (Percentage of Participants Alive) [Originally Phase III Primary / Now Phase II Secondary] | 69.3 percentage of participants |
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.
Population: Randomized participants
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| (Lead-in) RT + Durvalumab | Progression-free Survival (Percentage of Participants Alive Without Progression) [Phase II Primary] | 63.7 percentage of participants |
| RT + Durvalumab | Progression-free Survival (Percentage of Participants Alive Without Progression) [Phase II Primary] | 50.6 percentage of participants |
Change in Quality of Life (QOL) Analysis
Assessed using European Organization for Research and Treatment of Cancer Core Questionnaire (EORTC QLQ)/Head-and-Neck module (H&N35), EuroQol- 5 Dimension (EQ5D), M. D. Anderson Dysphagia Inventory (MDADI), patient reported outcomes (PRO)-CTCAE, geriatric screening (G8). The mean summary score of the EORTC QLQ/H&N35, EQ5D, MDADI, PRO-CTCAE, G8, CCI, and the subscales will be determined. 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: Baseline up to 12 months
Change in Swallowing QOL Using Total Composite M. D. Anderson Dysphagia Inventory (MDADI) Score
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.
Time frame: Baseline up to 1 year
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.
Population: Randomized participants
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| (Lead-in) RT + Durvalumab | Competing Mortality (Percentage of Participants Who Died Due to Causes Other Than Study Cancer) | 5.3 percentage of participants |
| RT + Durvalumab | Competing Mortality (Percentage of Participants Who Died Due to Causes Other Than Study Cancer) | 10.5 percentage of participants |
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.
Population: Randomized participants
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| (Lead-in) RT + Durvalumab | Distant Metastasis (Percentage of Participants With Distant Metastasis) | 12.1 percentage of participants |
| RT + Durvalumab | Distant Metastasis (Percentage of Participants With Distant Metastasis) | 9.5 percentage of participants |
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.
Population: Randomized participants
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| (Lead-in) RT + Durvalumab | Locoregional Failure (Percentage of Participants With Locoregional Failure) | 18.9 percentage of participants |
| RT + Durvalumab | Locoregional Failure (Percentage of Participants With Locoregional Failure) | 31.3 percentage of participants |
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.
Population: Randomized and started study treatment
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| (Lead-in) RT + Durvalumab | Number of Participants by Highest Grade Adverse Event Reported | < Grade 3 | 12 Participants |
| (Lead-in) RT + Durvalumab | Number of Participants by Highest Grade Adverse Event Reported | Grade 3 | 37 Participants |
| (Lead-in) RT + Durvalumab | Number of Participants by Highest Grade Adverse Event Reported | Grade 4 | 11 Participants |
| (Lead-in) RT + Durvalumab | Number of Participants by Highest Grade Adverse Event Reported | Grade 5 | 1 Participants |
| RT + Durvalumab | Number of Participants by Highest Grade Adverse Event Reported | Grade 5 | 11 Participants |
| RT + Durvalumab | Number of Participants by Highest Grade Adverse Event Reported | < Grade 3 | 36 Participants |
| RT + Durvalumab | Number of Participants by Highest Grade Adverse Event Reported | Grade 4 | 15 Participants |
| RT + Durvalumab | Number of Participants by Highest Grade Adverse Event Reported | Grade 3 | 57 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
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)
Population: Randomized participants with 4-month response assessed by PET
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| (Lead-in) 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 percentage of participants |
| 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 | 75.9 percentage of participants |
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.
Population: Randomized participants with p16 status.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| (Lead-in) RT + Durvalumab | Progression-free Survival (Percentage of Participants Alive Without Progression) by Baseline p16 Status | p16-positive | 74.8 percentage of participants |
| (Lead-in) RT + Durvalumab | Progression-free Survival (Percentage of Participants Alive Without Progression) by Baseline p16 Status | p16-negative | 48.1 percentage of participants |
| RT + Durvalumab | Progression-free Survival (Percentage of Participants Alive Without Progression) by Baseline p16 Status | p16-positive | 68.8 percentage of participants |
| RT + Durvalumab | Progression-free Survival (Percentage of Participants Alive Without Progression) by Baseline p16 Status | p16-negative | 23.2 percentage of participants |
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.
Population: Randomized participants with CPS score.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| (Lead-in) RT + Durvalumab | Progression-free Survival (Percentage of Participants Alive Without Progression) by Baseline PD-L1 (Programmed Cell Death Ligand 1) Expression | CPS ≥ 1 (PD-L1 expression) | 59.9 percentage of participants |
| (Lead-in) RT + Durvalumab | Progression-free Survival (Percentage of Participants Alive Without Progression) by Baseline PD-L1 (Programmed Cell Death Ligand 1) Expression | CPS = 0 (no PD-L1 expression) | 61.5 percentage of participants |
| RT + Durvalumab | Progression-free Survival (Percentage of Participants Alive Without Progression) by Baseline PD-L1 (Programmed Cell Death Ligand 1) Expression | CPS ≥ 1 (PD-L1 expression) | 54.8 percentage of participants |
| RT + Durvalumab | Progression-free Survival (Percentage of Participants Alive Without Progression) by Baseline PD-L1 (Programmed Cell Death Ligand 1) Expression | CPS = 0 (no PD-L1 expression) | 30.0 percentage of participants |
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
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