Study of Avelumab and Cetuximab Plus Gemcitabine and Cisplatin in Participants With NSCLC

• Avelumab (Drug): 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.
• Cetuximab (Drug): 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.
• Gemcitabine (Drug): 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.
• Cisplatin (Drug): 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.
• Carboplatin (Drug): 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.

Primary outcomes

• 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 outcomes

• 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.
• 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.
• 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.
• 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.

Sex: All, ages: 18 Years to any

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 exclusion criteria could apply

Participant flow

Outcome results

• Percentage of Participants With Confirmed Best Objective Response (BOR) According to Response Evaluation Criteria In Solid Tumors (RECIST) Version 1.1 Assessed by Investigator (Primary), Number, percentage of participants: Avelumab and Cetuximab 34.9 (21.0 to 50.9)
• 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) (Secondary), Count of participants, Participants: Avelumab and Cetuximab 41
• Progression-Free Survival (PFS) Time Per Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 (Secondary), Median, Months: Avelumab and Cetuximab 6.1 (4.3 to 9.0)
• Duration of Response (DOR) (Secondary), Median, Months: Avelumab and Cetuximab 7.1 (4.2 to 12.5)
• Immediate Observed Serum Concentration at End of Infusion (Ceoi) of Avelumab (Secondary), Geometric mean, microgram per milliliter (mcg/mL): Avelumab and Cetuximab 206 +/- 26.6
• Immediate Observed Serum Concentration at End of Infusion (Ceoi) of Cetuximab (Secondary), Geometric mean, mcg/mL: Avelumab and Cetuximab 109 +/- 50.7
• Serum Trough Concentration Levels (Ctrough) of Avelumab (Secondary), Geometric mean, mcg/mL: Avelumab and Cetuximab 28.8 +/- 82.7
• Serum Trough Concentration Levels (Ctrough) of Cetuximab (Secondary), Geometric mean, mcg/mL: Avelumab and Cetuximab 12.1 +/- 90.0
• Overall Survival (OS) (Secondary), Median, Months: Avelumab and Cetuximab 10.1 (8.6 to 14.5)
• Number of Participants With Positive Anti-Drug Antibody (ADA) of Avelumab (Secondary), Count of participants, Participants: Avelumab and Cetuximab 7
• Number of Participants With Positive Anti-Drug Antibody (ADA) of Cetuximab (Secondary), Count of participants, Participants: Avelumab and Cetuximab 1

Adverse events

Time frame: Time from the first dose of study drug until 941 days.

Serious adverse events by term

Other adverse events by term

• Results publication: Andric Z, Galffy G, Cobo Dols M, Szima B, Stojanovic G, Petrovic M, Felip E, Vicente Baz D, Ponce Aix S, Juan-Vidal O, Szalai Z, Losonczy G, Calles Blanco A, Bernabe R, Garcia Ledo G, Aguilar Hernandez A, Duecker K, Zhou D, Schroeder A, Guezel G, Ciardiello F. Avelumab in Combination With Cetuximab and Chemotherapy as First-Line Treatment for Patients With Advanced Squamous NSCLC. JTO Clin Res Rep. 2023 Jan 2;4(2):100461. doi: 10.1016/j.jtocrr.2022.100461. eCollection 2023 Feb. PMID 36718142

• Study Protocol (PDF, 2019-08-20)
• Statistical Analysis Plan (PDF, 2020-08-10)

• Medical Responsible, Study director, Merck KGaA, Darmstadt, Germany

NIH grants: 2018