A Study of Subcutaneous (SC) Pembrolizumab Coformulated With Hyaluronidase (MK-3475A) vs Intravenous Pembrolizumab in Adult Participants With Metastatic Non-small Cell Lung Cancer (NSCLC) (MK-3475A-D77)

Study Overview
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Brief Summary
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This study is to assess the pharmacokinetics (PK) and safety of SC MK-3475A vs intravenous (IV) pembrolizumab, administered with chemotherapy in first line treatment of adult participants with metastatic non-small cell lung cancer. The primary hypotheses of this study are MK-3475A subcutaneous (SC) is noninferior to pembrolizumab IV with respect to PK parameters.

Official Title
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A Phase 3 Randomized, Open-label Clinical Study to Evaluate the Pharmacokinetics and Safety of Subcutaneous Pembrolizumab Coformulated With Hyaluronidase (MK-3475A) Versus Intravenous Pembrolizumab, Administered With Chemotherapy, in the First-line Treatment of Participants With Metastatic Non-small Cell Lung Cancer

Conditions
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Metastatic Non-small Cell Lung Cancer

Intervention / Treatment
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* Biological: Pembrolizumab coformulated with hyaluronidase
* Drug: Pemetrexed
* Drug: Cisplatin
* Drug: Carboplatin
* Drug: Paclitaxel
* Drug: Nab-paclitaxel
* Biological: Pembrolizumab


Participation Criteria
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Eligibility Criteria
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The key inclusion and exclusion criteria include but are not limited to the following: Inclusion Criteria: Has histologically or cytologically confirmed diagnosis of squamous or non-squamous Non-small Cell Lung Cancer (NSCLC). Must provide archival tumor tissue sample or newly obtained core, incisional, or excisional biopsy of a tumor lesion not previously irradiated. Has a life expectancy of at least 3 months. Exclusion Criteria: Has a diagnosis of small cell lung cancer or, for mixed tumors, presence of small cell elements. Has received prior systemic anticancer therapy for metastatic NSCLC. Has received prior systemic anticancer therapy including investigational agents within 4 weeks before randomization. Has received prior radiotherapy within 2 weeks of start of study intervention or has radiation-related toxicity requiring corticosteroids. Has received radiation therapy to the lung (>30 Gray) within 6 months of start of study intervention. Has received a live or live-attenuated vaccine within 30 days before the first dose of study intervention. Has a diagnosis of immunodeficiency or is receiving chronic systemic steroid therapy. Has a known additional malignancy that is progressing or has required active treatment within the past 3 years. Has an active autoimmune disease that has required systemic treatment in past 2 years. Has an active infection requiring systemic therapy. Has a history of human immunodeficiency virus (HIV) infection. Has a history of Hepatitis B or C. Has not adequately recovered from major surgery or has ongoing surgical complications. Has a history of allogenic tissue/solid organ transplant.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Arm 1 (MK-3475A + Platinum Doublet Chemotherapy)<br>Participants with treatment-naïve metastatic NSCLC will receive MK 3475A SC in combination with platinum doublet chemotherapy. | Biological: Pembrolizumab coformulated with hyaluronidase<br>* MK3475A SC will be administered for squamous and nonsquamous NSCLC as per the schedule specified in arm; participants may be eligible for second course.<br>* Other names: MK-3475A;Drug: Pemetrexed<br>* Pemetrexed 500 mg/m² by IV Infusion will be administered for nonsquamous NSCLC as per the schedule specified in arm.<br>* Other names: Alimta;Drug: Cisplatin<br>* Cisplatin 75 mg/m² by IV Infusion will be administered for nonsquamous and squamous NSCLC as per the schedule specified in arm.<br>* Other names: Platinol-AQ;Drug: Carboplatin<br>* Carboplatin AUC 5 mg/mL/min in nonsquamous and AUC 6 mg/mL/min in squamous NSCLC will be administered as per the schedule specified in arm.<br>Drug: Paclitaxel<br>* Paclitaxel 200 mg/m² by IV Infusion will be administered for squamous NSCLC as per the schedule specified in arm.<br>* Other names: Taxol;Drug: Nab-paclitaxel<br>* Nab-paclitaxel 100 mg/m² by IV Infusion will be administered for squamous NSCLC as per the schedule specified in arm.<br>* Other names: Albumin-bound paclitaxel;|
| Active Comparator: Arm 2 (Pembrolizumab + Platinum Doublet Chemotherapy)<br>Participants with treatment-naïve metastatic NSCLC will receive Pembrolizumab IV in combination with platinum doublet chemotherapy. | Drug: Pemetrexed<br>* Pemetrexed 500 mg/m² by IV Infusion will be administered for nonsquamous NSCLC as per the schedule specified in arm.<br>* Other names: Alimta;Drug: Cisplatin<br>* Cisplatin 75 mg/m² by IV Infusion will be administered for nonsquamous and squamous NSCLC as per the schedule specified in arm.<br>* Other names: Platinol-AQ;Drug: Carboplatin<br>* Carboplatin AUC 5 mg/mL/min in nonsquamous and AUC 6 mg/mL/min in squamous NSCLC will be administered as per the schedule specified in arm.<br>Drug: Paclitaxel<br>* Paclitaxel 200 mg/m² by IV Infusion will be administered for squamous NSCLC as per the schedule specified in arm.<br>* Other names: Taxol;Drug: Nab-paclitaxel<br>* Nab-paclitaxel 100 mg/m² by IV Infusion will be administered for squamous NSCLC as per the schedule specified in arm.<br>* Other names: Albumin-bound paclitaxel;Biological: Pembrolizumab<br>* Pembrolizumab by IV Infusion will be administered for squamous and nonsquamous NSCLC as per the schedule specified in arm; participants may be eligible for second course.<br>* Other names: MK-3475, KEYTRUDA;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Area Under the Curve (AUC) of Pembrolizumab Measured After the First Dose | AUC is defined as area under curve exposure. Blood samples collected pre-dose and at multiple timepoints post-dose will be used to determine AUC. | At designated time points (Up to  14 months). | 
| Trough Concentration (Ctrough) of Pembrolizumab Measured at Steady State | Ctrough is defined as the trough concentration at steady-state. Blood samples collected pre-dose and at multiple timepoints post-dose will be used to determine Ctrough. | At designated time points (Up to  18 months) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Maximum Serum Concentration (Cmax) of Pembrolizumab Measured After the First Dose | Cmax is defined as the peak concentration over the dosing interval. Blood samples collected pre-dose and at multiple timepoints post-dose will be used to determine Cmax. | At designated time points (Up to  28 months) | 
| Trough Concentration (Ctrough) of Pembrolizumab Measured After the First Dose | Ctrough is defined as the trough concentration. Blood samples collected pre-dose and at multiple timepoints post-dose will be used to determine Ctrough. | At designated time points (Up to  28 months) | 
| Area Under the Curve (AUC) of Pembrolizumab Measured at Steady State | AUC is defined as area under curve exposure at steady state. Blood samples collected pre-dose and at multiple timepoints post-dose will be used to determine AUC. | At designated time points (Up to  28 months) | 
| Maximum Serum Concentration (Cmax) of Pembrolizumab Measured at Steady State | Cmax is defined as the peak concentration over the dosing interval in steady-state. Blood samples collected pre-dose and at multiple timepoints post-dose will be used to determine Cmax | At designated time points (Up to  28 months) | 
| Number of Participants Who Test Positive for Anti-Drug Antibodies (ADAs) for Pembrolizumab | Blood samples are to be collected at designated time points for the determination of the presence or absence of anti-pembrolizumab antibodies. The percentage of participants who develop anti pembrolizumab antibodies will be reported. | At designated time points (Up to  28 months) | 
| Objective Response Rate (ORR) per Response Evaluation Criteria In Solid Tumors Version 1.1 (RECIST 1.1) | The ORR is defined as the percentage of participants who achieve a confirmed CR or PR per RECIST 1.1 as assessed by BICR. | Up to 60 months | 
| Progression-free Survival (PFS) per Response Evaluation Criteria In Solid Tumors Version 1.1 (RECIST 1.1) | PFS is defined as the time from randomization to the first documented disease progression per RECIST 1.1 by BICR or death due to any cause, whichever occurs first. | Up to 60 months | 
| Overall Survival (OS) | OS is defined as the time from randomization to death due to any cause. | Up to 60 months | 
| Duration of Response (DOR) per Response Evaluation Criteria In Solid Tumors Version 1.1 (RECIST 1.1) | For participants who show confirmed CR or PR, DOR is defined as the time from the first documented evidence of CR or PR until disease progression or death due to any cause, whichever occurs first. | Up to 60 months | 
| Number of Participants Who Experienced at Least One Adverse Event (AE) | An AE is any untoward medical occurrence in a clinical study participant, temporally associated with the use of study intervention, whether or not considered related to the study intervention. The number of participants with an AE will be reported for Arms 1 and 2. | Up to 28 months | 
| Number of Participants Who Discontinued Study Treatment Due to an Adverse Event (AE) | An AE is any untoward medical occurrence in a clinical study participant, temporally associated with the use of study intervention, whether or not considered related to the study intervention. The number of participants who discontinue study treatment due to an AE will be reported for Arms 1 and 2. | Up to 25 months | 
| Change From Baseline in the European Organization for the Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire C30 (QLQ-C30) Global Health Status/Quality of Life (GHS/QoL) Score-Items 29 and 30 | EORTC QLQ-C30 is a psychometrically and clinically validated instrument appropriate for assessing HRQoL in oncology studies. The EORTC QLQ-C30 is the most widely used cancer-specific HRQoL instrument, which contains 30 items and measures 5 functional dimensions (physical, role, emotional, cognitive and social), 3 symptom items (fatigue, nausea/vomiting, and pain), 6 single items (dyspnea, sleep disturbance, appetite loss, constipation, diarrhea, and financial impact), and a global health and QoL scale. For the global health status or QoL and function scales, a higher value indicates a better level of function; for symptom scales and items, a higher value indicates increased severity of symptoms. | Baseline and up to  28 months | 
| Change From Baseline in the European Organization for the Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire C30 (QLQ-C30) Physical Functioning Score-Items 1 to 5 | The EQ-5D-5L is a standardized instrument for use as a measure of health outcome and will provide data to develop health utilities for use in health economic analyses. The 5 health state dimensions in the EQ-5D-5L include the following: Mobility, Self-Care, Usual Activities, Pain/Discomfort, and Anxiety/Depression. Each dimension is rated on a 5-point scale from 1 (no problem) to 5 (unable to/extreme problems). The EQ-5D-5L also includes a graded (0 to 100) vertical visual analog scale on which the participant rates his or her general state of health at the time of the assessment. This instrument has been used extensively in cancer studies and published results from these studies support its validity and reliability. | Baseline and up to  28 months | 
| Change From Baseline in the European Organization for the Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire C30 (QLQ-C30) Role Functioning Score-Items 6 and 7 | The EQ-5D-5L is a standardized instrument for use as a measure of health outcome and will provide data to develop health utilities for use in health economic analyses. The 5 health state dimensions in the EQ-5D-5L include the following: Mobility, Self-Care, Usual Activities, Pain/Discomfort, and Anxiety/Depression. Each dimension is rated on a 5-point scale from 1 (no problem) to 5 (unable to/extreme problems). The EQ-5D-5L also includes a graded (0 to 100) vertical visual analog scale on which the participant rates his or her general state of health at the time of the assessment. This instrument has been used extensively in cancer studies and published results from these studies support its validity and reliability. | Baseline and up to  28 months |