Squamous Non-Small Cell Lung Cancer
Conditions
Keywords
Avelumab, Cetuximab, Cisplatin, Gemcitabine, Non-Small Cell Lung Cancer
Brief summary
The main purpose of the study was to investigate the clinical activity and safety of avelumab in combination with cetuximab plus gemcitabine and cisplatin in participants with treatment-naïve advanced squamous non-small-cell lung cancer (NSCLC).
Interventions
DRUGAvelumab
Participants received avelumab intravenous infusions at a dose of 800 milligram (mg) on Day 1 and Day 8 of each 3-week cycle for the first 4 cycles. Thereafter, administered every 2 weeks in the Maintenance phase until disease progression or unacceptable toxicities.
DRUGCetuximab
Participants received cetuximab intravenous infusions at a dose of 250 milligram per meter square (mg/m\^2) body surface area on Day 1 and 500 mg/m\^2 body surface area on Day 8 of first 4 cycles of concurrent chemotherapy. Thereafter, administered given at a dose of 500 mg/m\^2 intravenous every 2 weeks in the Maintenance phase, until disease progression or unacceptable toxicities.
DRUGGemcitabine
Participants received gemcitabine intravenous infusions at a dose of 1250 mg/m\^2 body surface area on Day 1 and Day 8 in 3-week cycles up to a maximum of 4 cycles, until disease progression or unacceptable toxicities.
DRUGCisplatin
Participants received cisplatin intravenous infusions at a dose of 75 mg/m\^2 body surface area on Day 1 of 3-week cycles up to a maximum of 4 cycles, until disease progression or unacceptable toxicities.
DRUGCarboplatin
In case of cisplatin toxicities, participants were switched to carboplatin at a dose of target area under the serum concentration-time curve of 5 (AUC 5) on Day 1 for the remainder of cycles.
Sponsors
Merck KGaA, Darmstadt, Germany
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Histologically-confirmed Stage IV metastatic or recurrent (Stage IV) NSCLC of squamous histology * Availability of formalin-fixed paraffin-embedded (FFPE) block containing tumor tissue or a minimum of 15 (preferably 25) unstained tumor slides (cut within 1 week) suitable for Programmed death ligand 1 (PD-L1) expression and epidermal growth factor receptor (EGFR) expression/amplification assessments * At least 1 measurable lesion per response evaluation criteria in solid tumors (RECIST) v1.1 criteria * Eastern Cooperative Oncology Group Performance Status (ECOG PS) of 0 to 1 at study entry * Adequate hematological, hepatic and renal function * Estimated life expectancy of at least 3 months * Can give signed informed consent * Other protocol defined inclusion criteria could apply
Exclusion criteria
* Participants whose tumor disease harbors an activating EGFR mutation or ALK rearrangement. Participants with tumors of unknown EGFR or ALK status will require testing only in never smokers * All participants with brain metastases with protocol defined exceptions * Previous malignant disease (other than NSCLC) within the last 5 years (except adequately treated non-melanoma skin cancers, carcinoma in situ of skin, bladder, cervix, colon/rectum, breast, or prostate) unless a complete remission without further recurrence was achieved at least 2 years prior to study entry and the participant was deemed to have been cured with no additional therapy required or anticipated to be required * Active infection requiring systemic therapy * Known history of human immunodeficiency virus or known acquired immunodeficiency syndrome * Hepatitis B virus (HBV) or hepatitis C virus (HCV) infection at screening (positive HBV surface antigen or HCV ribonucleic acid (RNA) if anti-HCV antibody screening test positive) * Active autoimmune disease that might deteriorate when receiving an immunostimulatory agent * Interstitial parenchymal lung disease * Pregnancy or lactation * Known alcohol or drug abuse as determined by the Investigator * History of uncontrolled intercurrent illness * Clinically significant (that is active) cardiovascular disease * Known history of inflammatory colitis, inflammatory bowel disease, pneumonitis, pulmonary fibrosis * Any psychiatric condition that would prohibit the understanding or rendering of informed consent or that would limit compliance with study requirements * Prior/Concomitant Therapy as described in protocol * Use of any investigational drug within 28 days before the start of study treatment * Other protocol defined
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants With Confirmed Best Objective Response (BOR) According to Response Evaluation Criteria In Solid Tumors (RECIST) Version 1.1 Assessed by Investigator | Time from the first dose of study drug until occurrence of PD, death due to any cause (assessed up to 612 days) | Confirmed BOR was defined as the percentage of participants who achieved confirmed complete responses (CR) or partial response (PR), according to RECIST version 1.1 assessed by the Investigator.CR: Disappearance of all evidence of target and non-target lesions. PR: At least 30 percent (%) reduction from baseline in the sum of the longest diameter (SLD) of all lesions. Stable disease (SD)= Neither sufficient increase to qualify for progression of disease (PD) nor sufficient shrinkage to qualify for PR. PD: At least a 20 % increase in the SLD, taking as reference the smallest SLD recorded from baseline or the appearance of 1 or more new lesions. Confirmed CR=as at least two determinations of CR at least 4 weeks apart with no PD. Confirmed PR=as at least 2 determinations of PR or better (PR followed by PR or PR followed by CR), at least 4 weeks apart (not qualifying for a CR) with no PD in between. Percentage of Participants with confirmed BOR were reported. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Progression-Free Survival (PFS) Time Per Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 | Time from the first dose of study drug until occurrence of PD, death due to any cause (assessed up to 737 days) | Progression free survival (PFS) is defined as the time (in months) from first treatment day to the date of the first documentation of objective progression of disease (PD) according to RECIST version 1.1 assessed by Investigator, or death due to any cause, whichever occurs first. PD is defined as at least a 20 percent (%) increase in the SLD, taking as reference the smallest SLD recorded from baseline or the appearance of 1 or more new lesions. |
| Duration of Response (DOR) | Time from the first dose of study drug until occurrence of PD, death due to any cause or last tumor assessment (assessed up to 612 days) | DOR is defined for participants with confirmed complete response (CR) or partial response (PR), as the time from first documentation of confirmed response to the date of first documentation of progression of disease (PD) according to RECIST version 1.1 (assessed by Investigator) or death due to any cause or tumor assessment. Duration of objective response was assessed using Kaplan-Meier analysis. CR: Disappearance of all evidence of target and non-target lesions. PR: At least 30% reduction from baseline in the SLD of all lesions. PD: At least a 20 percent (%) increase in the SLD, taking as reference the smallest SLD recorded from baseline or the appearance of 1 or more new lesions. |
| Immediate Observed Serum Concentration at End of Infusion (Ceoi) of Avelumab | Pre-dose, 2 hours after end of infusion on Day 1, 8, 22 and 29; Pre-dose, 30 minutes after the end of infusion on Day 43, 50, 64, 71; Pre-dose, 3 hours after end of infusion on Day 85, 99, 113, 127, 169, 253, and 337 | Ceoi is the serum concentration observed immediately at the end of infusion. This was taken directly from the observed Avelumab concentration-time data. |
| Immediate Observed Serum Concentration at End of Infusion (Ceoi) of Cetuximab | Pre-dose, 2 hours after end of infusion on Day 1, 8, 22 and 29; Pre-dose, 30 minutes after the end of infusion on Day 43, 50, 64, 71; Pre-dose, 3 hours after end of infusion on Day 85, 99, 113, 127, 169, 253, and 337 | Ceoi is the serum concentration observed immediately at the end of infusion. This was taken directly from the observed cetuximab concentration-time data. |
| Number of Participants With Treatment-Emergent Adverse Events (TEAEs), Treatment-Related Adverse Events (AEs), Treatment-Related Grade >=3 TEAEs and Immune-related Treatment Emergent AEs (irTEAEs) | Time from the first dose of study drug assessed up to (941 days) | Adverse event (AE) was defined as any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease associated with the use of study drug, whether or not considered related to the study drug or worsening of pre-existing medical condition, whether or not related to study drug.Serious adverse event (SAE) was an AE that resulted in any of the following outcomes: death; life threatening; persistent/significant disability/incapacity; initial or prolonged inpatient hospitalization; congenital anomaly/birth defect or was otherwise considered medically important. TEAE is defined as AEs starting or worsening after the first intake of the study drug. TEAEs include both Serious and non-serious TEAEs. irAEs included AEs that matches a preferred term on the list of pre-selected MedDRA terms. AEs with relationship to study treatment are reported as Treatment-related AEs. Treatment related AEs with grade 3 or more is also reported. |
| Serum Trough Concentration Levels (Ctrough) of Cetuximab | Pre-dose: Day 8, Day 22, Day 29, Day 43, Day 50, Day 64, Day 71, Day 85, Day 99, Day 113, Day 127, Day 169, Day 253 and Day 337 | Ctrough is the serum concentration observed immediately before next dosing. |
| Overall Survival (OS) | Time from the first dose of study drug until occurrence of death due to any cause (assessed up to 941 days) | OS is defined as the time from the first treatment day to the date of death due to any cause. Overall survival was assessed using Kaplan-Meier analysis. |
| Number of Participants With Positive Anti-Drug Antibody (ADA) of Avelumab | Pre-dose up to 149 days | The detection of antibodies to avelumab was performed using a validated immunoassay method with tiered testing of screening, confirmatory and titration. Number of participants with positive anti-drug antibody (ADA) of avelumab were reported. |
| Number of Participants With Positive Anti-Drug Antibody (ADA) of Cetuximab | Pre-dose up to 149 days | The detection of antibodies to cetuximab was performed using a validated immunoassay method with tiered testing of screening, confirmatory and titration. Number of participants with positive anti-drug antibody (ADA) of cetuximab were reported. |
| Serum Trough Concentration Levels (Ctrough) of Avelumab | Pre-dose: Day 8, Day 22, Day 29, Day 43, Day 50, Day 64, Day 71, Day 85, Day 99, Day 113, Day 127, Day 169, Day 253 and Day 337 | Ctrough is the serum concentration observed immediately before next dosing. |
Countries
Hungary, Serbia, Spain
Participant flow
Pre-assignment details
A total of 43 participants were enrolled in this study at different sites in Hungary, Serbia and Spain.
Participants by arm
| Arm | Count |
|---|---|
| Avelumab and Cetuximab Participants received 800 milligrams Avelumab, 1250 milligrams per square meter (mg/m\^2) gemcitabine on Day 1 and Day 8, cisplatin at a dose of 75 mg/m\^2 on Day 1 along with 250 mg/m2 body surface area Cetuximab on Day 1 and 500 mg/m2 body surface area on Day 8 of each cycle as intravenous (IV) infusions up to maximum of 4 cycles (each cycle is of 3 weeks) until disease progression or unacceptable toxicities. In case of cisplatin toxicities, participants were switched to carboplatin at a dose of target area under the serum concentration-time curve of 5 (AUC 5) on Day 1 for the remainder of cycles. Subsequently participants were administered with avelumab and cetuximab as IV infusion at the dose of 800 mg and 500 mg/m\^2 respectively, every 2 weeks in the Maintenance phase until disease progression or unacceptable toxicities. | 43 |
| Total | 43 |
Baseline characteristics
| Characteristic | Avelumab and Cetuximab |
|---|---|
| Age, Continuous | 63 Years STANDARD_DEVIATION 7.2 |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) White | 43 Participants |
| Sex: Female, Male Female | 8 Participants |
| Sex: Female, Male Male | 35 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 30 / 43 |
| other Total, other adverse events | 39 / 43 |
| serious Total, serious adverse events | 20 / 43 |
Outcome results
Primary
Percentage of Participants With Confirmed Best Objective Response (BOR) According to Response Evaluation Criteria In Solid Tumors (RECIST) Version 1.1 Assessed by Investigator
Confirmed BOR was defined as the percentage of participants who achieved confirmed complete responses (CR) or partial response (PR), according to RECIST version 1.1 assessed by the Investigator.CR: Disappearance of all evidence of target and non-target lesions. PR: At least 30 percent (%) reduction from baseline in the sum of the longest diameter (SLD) of all lesions. Stable disease (SD)= Neither sufficient increase to qualify for progression of disease (PD) nor sufficient shrinkage to qualify for PR. PD: At least a 20 % increase in the SLD, taking as reference the smallest SLD recorded from baseline or the appearance of 1 or more new lesions. Confirmed CR=as at least two determinations of CR at least 4 weeks apart with no PD. Confirmed PR=as at least 2 determinations of PR or better (PR followed by PR or PR followed by CR), at least 4 weeks apart (not qualifying for a CR) with no PD in between. Percentage of Participants with confirmed BOR were reported.
Time frame: Time from the first dose of study drug until occurrence of PD, death due to any cause (assessed up to 612 days)
Population: Full analysis set includes all participants who received at least one non-zero dose of any study treatment.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Avelumab and Cetuximab | Percentage of Participants With Confirmed Best Objective Response (BOR) According to Response Evaluation Criteria In Solid Tumors (RECIST) Version 1.1 Assessed by Investigator | 34.9 percentage of participants |
Secondary
Duration of Response (DOR)
DOR is defined for participants with confirmed complete response (CR) or partial response (PR), as the time from first documentation of confirmed response to the date of first documentation of progression of disease (PD) according to RECIST version 1.1 (assessed by Investigator) or death due to any cause or tumor assessment. Duration of objective response was assessed using Kaplan-Meier analysis. CR: Disappearance of all evidence of target and non-target lesions. PR: At least 30% reduction from baseline in the SLD of all lesions. PD: At least a 20 percent (%) increase in the SLD, taking as reference the smallest SLD recorded from baseline or the appearance of 1 or more new lesions.
Time frame: Time from the first dose of study drug until occurrence of PD, death due to any cause or last tumor assessment (assessed up to 612 days)
Population: Full analysis set included all participants who receive at least one non-zero dose of any study treatment. Here Overall number of participants analyzed signifies those participants who had confirmed CR or PR.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Avelumab and Cetuximab | Duration of Response (DOR) | 7.1 Months |
Secondary
Immediate Observed Serum Concentration at End of Infusion (Ceoi) of Avelumab
Ceoi is the serum concentration observed immediately at the end of infusion. This was taken directly from the observed Avelumab concentration-time data.
Time frame: Pre-dose, 2 hours after end of infusion on Day 1, 8, 22 and 29; Pre-dose, 30 minutes after the end of infusion on Day 43, 50, 64, 71; Pre-dose, 3 hours after end of infusion on Day 85, 99, 113, 127, 169, 253, and 337
Population: Pharmacokinetic (PK) analysis set included all participants who receive at least one dose of avelumab and/or cetuximab, have no important events affecting PK, and provide at least one measurable post-dose concentration. Number of Participants Analyzed=participants evaluable for this outcome and Number analyzed=participants evaluated at specified time point.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Avelumab and Cetuximab | Immediate Observed Serum Concentration at End of Infusion (Ceoi) of Avelumab | Day 1 | 206 microgram per milliliter (mcg/mL) | Geometric Coefficient of Variation 26.6 |
| Avelumab and Cetuximab | Immediate Observed Serum Concentration at End of Infusion (Ceoi) of Avelumab | Day 8 | 243 microgram per milliliter (mcg/mL) | Geometric Coefficient of Variation 23.8 |
| Avelumab and Cetuximab | Immediate Observed Serum Concentration at End of Infusion (Ceoi) of Avelumab | Day 22 | 234 microgram per milliliter (mcg/mL) | Geometric Coefficient of Variation 24.1 |
| Avelumab and Cetuximab | Immediate Observed Serum Concentration at End of Infusion (Ceoi) of Avelumab | Day 29 | 282 microgram per milliliter (mcg/mL) | Geometric Coefficient of Variation 26.8 |
| Avelumab and Cetuximab | Immediate Observed Serum Concentration at End of Infusion (Ceoi) of Avelumab | Day 43 | 237 microgram per milliliter (mcg/mL) | Geometric Coefficient of Variation 30.5 |
| Avelumab and Cetuximab | Immediate Observed Serum Concentration at End of Infusion (Ceoi) of Avelumab | Day 50 | 259 microgram per milliliter (mcg/mL) | Geometric Coefficient of Variation 38.9 |
| Avelumab and Cetuximab | Immediate Observed Serum Concentration at End of Infusion (Ceoi) of Avelumab | Day 64 | 214 microgram per milliliter (mcg/mL) | Geometric Coefficient of Variation 67.6 |
| Avelumab and Cetuximab | Immediate Observed Serum Concentration at End of Infusion (Ceoi) of Avelumab | Day 71 | 244 microgram per milliliter (mcg/mL) | Geometric Coefficient of Variation 43.8 |
| Avelumab and Cetuximab | Immediate Observed Serum Concentration at End of Infusion (Ceoi) of Avelumab | Day 85 | 223 microgram per milliliter (mcg/mL) | Geometric Coefficient of Variation 33.3 |
| Avelumab and Cetuximab | Immediate Observed Serum Concentration at End of Infusion (Ceoi) of Avelumab | Day 99 | 202 microgram per milliliter (mcg/mL) | Geometric Coefficient of Variation 62.4 |
| Avelumab and Cetuximab | Immediate Observed Serum Concentration at End of Infusion (Ceoi) of Avelumab | Day 113 | 234 microgram per milliliter (mcg/mL) | Geometric Coefficient of Variation 29.7 |
| Avelumab and Cetuximab | Immediate Observed Serum Concentration at End of Infusion (Ceoi) of Avelumab | Day 127 | 222 microgram per milliliter (mcg/mL) | Geometric Coefficient of Variation 55.1 |
| Avelumab and Cetuximab | Immediate Observed Serum Concentration at End of Infusion (Ceoi) of Avelumab | Day 169 | 245 microgram per milliliter (mcg/mL) | Geometric Coefficient of Variation 20.8 |
| Avelumab and Cetuximab | Immediate Observed Serum Concentration at End of Infusion (Ceoi) of Avelumab | Day 253 | 249 microgram per milliliter (mcg/mL) | Geometric Coefficient of Variation 28.7 |
| Avelumab and Cetuximab | Immediate Observed Serum Concentration at End of Infusion (Ceoi) of Avelumab | Day 337 | 246 microgram per milliliter (mcg/mL) | Geometric Coefficient of Variation 38.6 |
Secondary
Immediate Observed Serum Concentration at End of Infusion (Ceoi) of Cetuximab
Ceoi is the serum concentration observed immediately at the end of infusion. This was taken directly from the observed cetuximab concentration-time data.
Time frame: Pre-dose, 2 hours after end of infusion on Day 1, 8, 22 and 29; Pre-dose, 30 minutes after the end of infusion on Day 43, 50, 64, 71; Pre-dose, 3 hours after end of infusion on Day 85, 99, 113, 127, 169, 253, and 337
Population: PK analysis set included all participants who receive at least one dose of avelumab and/or cetuximab, have no important events affecting PK, and provide at least one measurable post-dose concentration. Number analyzed=participants evaluated at specified time point.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Avelumab and Cetuximab | Immediate Observed Serum Concentration at End of Infusion (Ceoi) of Cetuximab | Day 1 | 109 mcg/mL | Geometric Coefficient of Variation 50.7 |
| Avelumab and Cetuximab | Immediate Observed Serum Concentration at End of Infusion (Ceoi) of Cetuximab | Day 8 | 198 mcg/mL | Geometric Coefficient of Variation 86.6 |
| Avelumab and Cetuximab | Immediate Observed Serum Concentration at End of Infusion (Ceoi) of Cetuximab | Day 22 | 124 mcg/mL | Geometric Coefficient of Variation 54.4 |
| Avelumab and Cetuximab | Immediate Observed Serum Concentration at End of Infusion (Ceoi) of Cetuximab | Day 29 | 260 mcg/mL | Geometric Coefficient of Variation 25 |
| Avelumab and Cetuximab | Immediate Observed Serum Concentration at End of Infusion (Ceoi) of Cetuximab | Day 43 | 154 mcg/mL | Geometric Coefficient of Variation 32.7 |
| Avelumab and Cetuximab | Immediate Observed Serum Concentration at End of Infusion (Ceoi) of Cetuximab | Day 50 | 238 mcg/mL | Geometric Coefficient of Variation 28.9 |
| Avelumab and Cetuximab | Immediate Observed Serum Concentration at End of Infusion (Ceoi) of Cetuximab | Day 64 | 159 mcg/mL | Geometric Coefficient of Variation 36.1 |
| Avelumab and Cetuximab | Immediate Observed Serum Concentration at End of Infusion (Ceoi) of Cetuximab | Day 71 | 262 mcg/mL | Geometric Coefficient of Variation 25.1 |
| Avelumab and Cetuximab | Immediate Observed Serum Concentration at End of Infusion (Ceoi) of Cetuximab | Day 85 | 239 mcg/mL | Geometric Coefficient of Variation 38.4 |
| Avelumab and Cetuximab | Immediate Observed Serum Concentration at End of Infusion (Ceoi) of Cetuximab | Day 99 | 252 mcg/mL | Geometric Coefficient of Variation 21.1 |
| Avelumab and Cetuximab | Immediate Observed Serum Concentration at End of Infusion (Ceoi) of Cetuximab | Day 113 | 250 mcg/mL | Geometric Coefficient of Variation 20.4 |
| Avelumab and Cetuximab | Immediate Observed Serum Concentration at End of Infusion (Ceoi) of Cetuximab | Day 127 | 245 mcg/mL | Geometric Coefficient of Variation 55.8 |
| Avelumab and Cetuximab | Immediate Observed Serum Concentration at End of Infusion (Ceoi) of Cetuximab | Day 169 | 297 mcg/mL | Geometric Coefficient of Variation 29.2 |
| Avelumab and Cetuximab | Immediate Observed Serum Concentration at End of Infusion (Ceoi) of Cetuximab | Day 253 | 269 mcg/mL | Geometric Coefficient of Variation 34.4 |
| Avelumab and Cetuximab | Immediate Observed Serum Concentration at End of Infusion (Ceoi) of Cetuximab | Day 337 | 304 mcg/mL | Geometric Coefficient of Variation 37.3 |
Secondary
Number of Participants With Positive Anti-Drug Antibody (ADA) of Avelumab
The detection of antibodies to avelumab was performed using a validated immunoassay method with tiered testing of screening, confirmatory and titration. Number of participants with positive anti-drug antibody (ADA) of avelumab were reported.
Time frame: Pre-dose up to 149 days
Population: ADA analysis set included all participants who received at least 1 dose of avelumab and/or cetuximab and have at least 1 valid ADA result.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Avelumab and Cetuximab | Number of Participants With Positive Anti-Drug Antibody (ADA) of Avelumab | 7 Participants |
Secondary
Number of Participants With Positive Anti-Drug Antibody (ADA) of Cetuximab
The detection of antibodies to cetuximab was performed using a validated immunoassay method with tiered testing of screening, confirmatory and titration. Number of participants with positive anti-drug antibody (ADA) of cetuximab were reported.
Time frame: Pre-dose up to 149 days
Population: ADA analysis set included all participants who received at least 1 dose of avelumab and/or cetuximab and have at least 1 valid ADA result.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Avelumab and Cetuximab | Number of Participants With Positive Anti-Drug Antibody (ADA) of Cetuximab | 1 Participants |
Secondary
Number of Participants With Treatment-Emergent Adverse Events (TEAEs), Treatment-Related Adverse Events (AEs), Treatment-Related Grade >=3 TEAEs and Immune-related Treatment Emergent AEs (irTEAEs)
Adverse event (AE) was defined as any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease associated with the use of study drug, whether or not considered related to the study drug or worsening of pre-existing medical condition, whether or not related to study drug.Serious adverse event (SAE) was an AE that resulted in any of the following outcomes: death; life threatening; persistent/significant disability/incapacity; initial or prolonged inpatient hospitalization; congenital anomaly/birth defect or was otherwise considered medically important. TEAE is defined as AEs starting or worsening after the first intake of the study drug. TEAEs include both Serious and non-serious TEAEs. irAEs included AEs that matches a preferred term on the list of pre-selected MedDRA terms. AEs with relationship to study treatment are reported as Treatment-related AEs. Treatment related AEs with grade 3 or more is also reported.
Time frame: Time from the first dose of study drug assessed up to (941 days)
Population: Safety analysis set included all participants who received at least one non-zero dose of any study treatment.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Avelumab and Cetuximab | Number of Participants With Treatment-Emergent Adverse Events (TEAEs), Treatment-Related Adverse Events (AEs), Treatment-Related Grade >=3 TEAEs and Immune-related Treatment Emergent AEs (irTEAEs) | TEAEs | 41 Participants |
| Avelumab and Cetuximab | Number of Participants With Treatment-Emergent Adverse Events (TEAEs), Treatment-Related Adverse Events (AEs), Treatment-Related Grade >=3 TEAEs and Immune-related Treatment Emergent AEs (irTEAEs) | Treatment-Related AEs | 38 Participants |
| Avelumab and Cetuximab | Number of Participants With Treatment-Emergent Adverse Events (TEAEs), Treatment-Related Adverse Events (AEs), Treatment-Related Grade >=3 TEAEs and Immune-related Treatment Emergent AEs (irTEAEs) | Treatment Related Grade>=3 TEAEs | 24 Participants |
| Avelumab and Cetuximab | Number of Participants With Treatment-Emergent Adverse Events (TEAEs), Treatment-Related Adverse Events (AEs), Treatment-Related Grade >=3 TEAEs and Immune-related Treatment Emergent AEs (irTEAEs) | irTEAEs | 13 Participants |
Secondary
Overall Survival (OS)
OS is defined as the time from the first treatment day to the date of death due to any cause. Overall survival was assessed using Kaplan-Meier analysis.
Time frame: Time from the first dose of study drug until occurrence of death due to any cause (assessed up to 941 days)
Population: Full analysis set includes all participants who received at least one non-zero dose of any study treatment.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Avelumab and Cetuximab | Overall Survival (OS) | 10.1 Months |
Secondary
Progression-Free Survival (PFS) Time Per Response Evaluation Criteria in Solid Tumors (RECIST) 1.1
Progression free survival (PFS) is defined as the time (in months) from first treatment day to the date of the first documentation of objective progression of disease (PD) according to RECIST version 1.1 assessed by Investigator, or death due to any cause, whichever occurs first. PD is defined as at least a 20 percent (%) increase in the SLD, taking as reference the smallest SLD recorded from baseline or the appearance of 1 or more new lesions.
Time frame: Time from the first dose of study drug until occurrence of PD, death due to any cause (assessed up to 737 days)
Population: Full analysis set includes all participants who received at least one non-zero dose of any study treatment.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Avelumab and Cetuximab | Progression-Free Survival (PFS) Time Per Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 | 6.1 Months |
Secondary
Serum Trough Concentration Levels (Ctrough) of Avelumab
Ctrough is the serum concentration observed immediately before next dosing.
Time frame: Pre-dose: Day 8, Day 22, Day 29, Day 43, Day 50, Day 64, Day 71, Day 85, Day 99, Day 113, Day 127, Day 169, Day 253 and Day 337
Population: PK analysis set included all participants who receive at least one dose of avelumab and/or cetuximab, have no important events affecting PK, and provide at least one measurable post-dose concentration. Number of Participants Analyzed=participants evaluable for this outcome and Number analyzed=participants evaluated at specified time point.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Avelumab and Cetuximab | Serum Trough Concentration Levels (Ctrough) of Avelumab | Day 8 | 28.8 mcg/mL | Geometric Coefficient of Variation 82.7 |
| Avelumab and Cetuximab | Serum Trough Concentration Levels (Ctrough) of Avelumab | Day 22 | 13.6 mcg/mL | Geometric Coefficient of Variation 97.1 |
| Avelumab and Cetuximab | Serum Trough Concentration Levels (Ctrough) of Avelumab | Day 29 | 42.4 mcg/mL | Geometric Coefficient of Variation 147.8 |
| Avelumab and Cetuximab | Serum Trough Concentration Levels (Ctrough) of Avelumab | Day 43 | 15.6 mcg/mL | Geometric Coefficient of Variation 115.1 |
| Avelumab and Cetuximab | Serum Trough Concentration Levels (Ctrough) of Avelumab | Day 50 | 56.4 mcg/mL | Geometric Coefficient of Variation 77.9 |
| Avelumab and Cetuximab | Serum Trough Concentration Levels (Ctrough) of Avelumab | Day 64 | 19.7 mcg/mL | Geometric Coefficient of Variation 145.7 |
| Avelumab and Cetuximab | Serum Trough Concentration Levels (Ctrough) of Avelumab | Day 71 | 58.2 mcg/mL | Geometric Coefficient of Variation 62.5 |
| Avelumab and Cetuximab | Serum Trough Concentration Levels (Ctrough) of Avelumab | Day 85 | 21.5 mcg/mL | Geometric Coefficient of Variation 70.9 |
| Avelumab and Cetuximab | Serum Trough Concentration Levels (Ctrough) of Avelumab | Day 99 | 21.2 mcg/mL | Geometric Coefficient of Variation 75.4 |
| Avelumab and Cetuximab | Serum Trough Concentration Levels (Ctrough) of Avelumab | Day 113 | 19.4 mcg/mL | Geometric Coefficient of Variation 78.5 |
| Avelumab and Cetuximab | Serum Trough Concentration Levels (Ctrough) of Avelumab | Day 127 | 18.1 mcg/mL | Geometric Coefficient of Variation 107.6 |
| Avelumab and Cetuximab | Serum Trough Concentration Levels (Ctrough) of Avelumab | Day 169 | 19.3 mcg/mL | Geometric Coefficient of Variation 67.2 |
| Avelumab and Cetuximab | Serum Trough Concentration Levels (Ctrough) of Avelumab | Day 253 | 17.0 mcg/mL | Geometric Coefficient of Variation 80.1 |
| Avelumab and Cetuximab | Serum Trough Concentration Levels (Ctrough) of Avelumab | Day 337 | 20.8 mcg/mL | Geometric Coefficient of Variation 55.9 |
Secondary
Serum Trough Concentration Levels (Ctrough) of Cetuximab
Ctrough is the serum concentration observed immediately before next dosing.
Time frame: Pre-dose: Day 8, Day 22, Day 29, Day 43, Day 50, Day 64, Day 71, Day 85, Day 99, Day 113, Day 127, Day 169, Day 253 and Day 337
Population: PK analysis set included all participants who receive at least one dose of avelumab and/or cetuximab, have no important events affecting PK, and provide at least one measurable post-dose concentration. Number of Participants Analyzed=participants evaluable for this outcome and Number analyzed=participants evaluated at specified time point.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Avelumab and Cetuximab | Serum Trough Concentration Levels (Ctrough) of Cetuximab | Day 8 | 12.1 mcg/mL | Geometric Coefficient of Variation 90 |
| Avelumab and Cetuximab | Serum Trough Concentration Levels (Ctrough) of Cetuximab | Day 22 | 12.8 mcg/mL | Geometric Coefficient of Variation 63.7 |
| Avelumab and Cetuximab | Serum Trough Concentration Levels (Ctrough) of Cetuximab | Day 29 | 22.8 mcg/mL | Geometric Coefficient of Variation 73.3 |
| Avelumab and Cetuximab | Serum Trough Concentration Levels (Ctrough) of Cetuximab | Day 43 | 25.6 mcg/mL | Geometric Coefficient of Variation 103.7 |
| Avelumab and Cetuximab | Serum Trough Concentration Levels (Ctrough) of Cetuximab | Day 50 | 23.9 mcg/mL | Geometric Coefficient of Variation 118.1 |
| Avelumab and Cetuximab | Serum Trough Concentration Levels (Ctrough) of Cetuximab | Day 64 | 17.2 mcg/mL | Geometric Coefficient of Variation 157.9 |
| Avelumab and Cetuximab | Serum Trough Concentration Levels (Ctrough) of Cetuximab | Day 71 | 35.4 mcg/mL | Geometric Coefficient of Variation 110.4 |
| Avelumab and Cetuximab | Serum Trough Concentration Levels (Ctrough) of Cetuximab | Day 85 | 26.5 mcg/mL | Geometric Coefficient of Variation 119.4 |
| Avelumab and Cetuximab | Serum Trough Concentration Levels (Ctrough) of Cetuximab | Day 99 | 22.6 mcg/mL | Geometric Coefficient of Variation 117.3 |
| Avelumab and Cetuximab | Serum Trough Concentration Levels (Ctrough) of Cetuximab | Day 113 | 35.0 mcg/mL | Geometric Coefficient of Variation 59 |
| Avelumab and Cetuximab | Serum Trough Concentration Levels (Ctrough) of Cetuximab | Day 127 | 38.0 mcg/mL | Geometric Coefficient of Variation 63.6 |
| Avelumab and Cetuximab | Serum Trough Concentration Levels (Ctrough) of Cetuximab | Day 169 | 40.4 mcg/mL | Geometric Coefficient of Variation 62.2 |
| Avelumab and Cetuximab | Serum Trough Concentration Levels (Ctrough) of Cetuximab | Day 253 | 31.9 mcg/mL | Geometric Coefficient of Variation 237.7 |
| Avelumab and Cetuximab | Serum Trough Concentration Levels (Ctrough) of Cetuximab | Day 337 | 28.9 mcg/mL | Geometric Coefficient of Variation 204.9 |