MK-2870 Versus Chemotherapy in Previously Treated Advanced or Metastatic Nonsquamous Non-small Cell Lung Cancer (NSCLC) With EGFR Mutations or Other Genomic Alterations (MK-2870-004)

Study Overview
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Brief Summary
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The purpose of this study is to evaluate MK-2870 versus chemotherapy (docetaxel or pemetrexed) for the treatment of previously-treated non-small cell lung cancer (NSCLC) with exon 19del or exon 21 L858R EGFR mutations (hereafter referred to as EGFR mutations or EGFR-mutated) or any of the follow genomic alterations: ALK gene rearrangements, ROS1 rearrangements, BRAF V600E mutations, NTRK gene fusions, MET exon 14 skipping mutations, RET rearrangements, or less common EGFR point mutations of exon 20 S768I, exon 21 L861Q, or exon 18 G719X mutations. The primary hypotheses are that MK-2870 is: (1) superior to chemotherapy with respect to progression-free survival (PFS) per RECIST 1.1 as assessed by BICR in NSCLC with EGFR mutations; and (2) superior to chemotherapy with respect to overall survival (OS) in NSCLC with EGFR mutations.

Official Title
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A Randomized, Open-label, Phase 3 Study of MK-2870 vs Chemotherapy (Docetaxel or Pemetrexed) in Previously Treated Advanced or Metastatic Nonsquamous Non-small Cell Lung Cancer (NSCLC) With EGFR Mutations or Other Genomic Alterations

Conditions
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Non-small Cell Lung Cancer (NSCLC)

Intervention / Treatment
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* Biological: MK-2870
* Drug: Docetaxel
* Drug: Pemetrexed


Participation Criteria
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Eligibility Criteria
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The main inclusion and exclusion criteria include but are not limited to the following: Inclusion Criteria: Histologically- or cytologically-documented advanced (Stage III not eligible for resection or curative radiation) or metastatic non-squamous NSCLC with specific mutations. Documentation of locally assessed radiological disease progression while on or after last treatment based on Response Evaluation Criteria in Solid Tumors Version (RECIST) 1.1. Participants with genome mutations must have received 1 or 2 prior lines of epidermal growth factor receptor tyrosine kinase inhibitor (EGFR TKI), including a third generation TKI for participants with a T790M mutation; and 1 platinum-based therapy after progression on or after EGFR TKI. Measurable disease per RECIST 1.1 as assessed by the local site investigator. Archival tumor tissue sample or newly obtained core, incisional, or excisional biopsy of a tumor lesion not previously irradiated has been provided Participants who have AEs due to previous anticancer therapies must have recovered to Grade ≤1 or baseline. Participants who are hepatitis B surface antigen (HBsAg) positive are eligible if they have received HBV antiviral therapy for at least 4 weeks, and have undetectable HBV viral load prior to randomization. Human immunodeficiency virus (HIV)-infected participants must have well controlled HIV on antiretroviral therapy. Have an ECOG performance status of 0 or 1 within 3 days before randomization. Exclusion Criteria: Has predominantly squamous cell histology NSCLC. Has mixed tumor(s) with small cell elements. Has active inflammatory bowel disease requiring immunosuppressive medication or previous history of inflammatory bowel disease. Has Grade ≥2 peripheral neuropathy. Has history of documented severe dry eye syndrome, severe Meibomian gland disease and/or blepharitis, or corneal disease that prevents/delays corneal healing. Has uncontrolled, significant cardiovascular disease or cerebrovascular disease. Has an EGFR T790M mutation and has not received a third generation EGFR TKI (eg, osimertinib). Received prior systemic anticancer therapy including investigational agents within 4 weeks or 5 half-lives (whichever is shorter) before randomization. Received a live or live-attenuated vaccine within 30 days before the first dose of study intervention. Completed palliative radiotherapy within 7 days of the first dose. Participants must have recovered from all radiation-related toxicities and not require corticosteroids. Received radiation therapy to the lung that is >30 Gy within 6 months of the first dose of study intervention. Received prior treatment with a trophoblast cell-surface antigen 2 (TROP2)-targeted antibody-drug conjugate (ADC). Received prior treatment with a topoisomerase I-containing ADC. Has received an investigational agent or has used an investigational device within 4 weeks prior to study intervention administration. Known additional malignancy that is progressing or has required active treatment within the past 3 years. Active infection requiring systemic therapy. History of noninfectious pneumonitis/ILD that required steroids or has current pneumonitis/ILD. Has known active central nervous system metastases and/or carcinomatous meningitis. Participants with previously treated brain metastases may participate provided they are clinically stable for at least 2 weeks, and are off steroids 3 days prior to dosing with study medication. HIV-infected participants with a history of Kaposi's sarcoma and/or Multicentric Castleman's Disease. Concurrent active Hepatitis B (defined as HBsAg positive and/or detectable HBV DNA) and Hepatitis C virus (defined as anti-HCV Ab positive and detectable HCV RNA) infection.

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: MK-2870<br>Participants will receive 4 mg/kg of MK-2870 via intravenous (IV) infusion on Days 1, 15 and 29 of each 6-week cycle. Additionally, participants receive diphenhydramine (or equivalent), an H2 antagonist of investigator's choice, acetaminophen (or equivalent), and dexamethasone (or equivalent) per each drug's product label prior to the first 4 infusions of MK-2870. At subsequent infusions, the H2 antagonist and dexamethasone are optional, at the discretion of the investigator. | Biological: MK-2870<br>* 4 mg/kg of MK-2870 by IV infusion<br>* Other names: SKB264;|
| Active Comparator: Chemotherapy<br>Participants will receive 75 mg/m^2 of docetaxel or 500 mg/m^2 of pemetrexed by IV infusion on Days 1 and 22 of every 6-week cycle. | Drug: Docetaxel<br>* 75 mg/m^2 of docetaxel by IV Infusion<br>* Other names: TAXOTERE®;Drug: Pemetrexed<br>* 500 mg/m^2 of pemetrexed by IV infusion<br>* Other names: ALIMTA®;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression-free Survival (PFS) of Participants with NSCLC with Epidermal Growth Factor Receptor (EGFR) Mutations | PFS is defined as the time from randomization to the first documented disease progression per RECIST 1.1 based on blinded independent central review (BICR) or death due to any cause, whichever occurs first. | Up to approximately 6 years | 
| Overall Survival (OS) of Participants with NSCLC with EGFR mutations | OS is defined as the time from randomization to death due to any cause. | Up to approximately 6 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| PFS of All Participants with NSCLC | PFS is defined as the time from randomization to the first documented disease progression per RECIST 1.1 based on BICR or death due to any cause, whichever occurs first. | Up to approximately 6 years | 
| OS of All Participants with NSCLC | OS is defined as the time from randomization to death due to any cause. | Up to approximately 6 years | 
| Objective Response Rate (ORR) of Participants with NSCLC with EGFR Mutations | ORR was defined as the percentage of participants who had a Complete Response (CR: Disappearance of all target lesions) or a Partial Response (PR: At least a 30% decrease in the sum of diameters of target lesions) as assessed using RECIST 1.1. based on BICR in NSCLC with EGFR mutations. | Up to approximately 6 years | 
| ORR of All Participants with NSCLC | ORR was defined as the percentage of participants who had a Complete Response (CR: Disappearance of all target lesions) or a Partial Response (PR: At least a 30% decrease in the sum of diameters of target lesions) as assessed using RECIST 1.1. based on BICR in all participants with NSCLC. | Up to approximately 6 years | 
| Duration of Response (DOR) of All Participants with NSCLC | For participants who demonstrate confirmed CR or PR per RECIST 1.1 as assessed by BICR in all participants with NSCLC, 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 approximately 6 years | 
| Change in Score from Baseline in Global Health Status/QoL Score (European Organisation for Research and Treatment of Cancer [EORTC] Quality of Life Questionnaire-Core 30 [QLQ-C30] Items 29 and 30) | The EORTC QLQ-C30 is a questionnaire to assess the overall health status and quality of life of cancer patients. Participant responses to the questions How would you rate your overall health during the past week? and How would you rate your overall quality of life during the past week? are scored on a 7-point scale (1= Very poor to 7=Excellent). Using linear transformation, raw scores are standardized, so that scores range from 0 to 100. A higher score indicates a better overall health status and quality of life. The change from baseline in EORTC QLQ-C30 Items 29 and 30 combined score will be presented. | Baseline and up to approximately 48 weeks | 
| Change in Score from Baseline in Dyspnea Score (EORTC QLQ-C30 Item 8) | The EORTC QLQ-C30 is a cancer specific health-related quality-of life (QoL) questionnaire. Participant response to the question Were you short of breath? is scored on a 4-point scale (1=Not at All to 4=Very Much). A higher score indicates a worse level of dyspnea. The change from baseline in the dyspnea (EORTC QLQ-C30 Item 8) score will be presented. | Baseline and up to approximately 48 weeks | 
| Change in Score from Baseline in Cough (EORTC Quality of Life Questionnaire-Lung Cancer 13 [QLQ-LC13] Item 31) | The EORTC QLQ-LC13 is a lung cancer-specific supplemental questionnaire used in combination with the EORTC QLQ-C30. Participant responses to the question How much did you cough? are scored on a 4-point scale (1=Not at All to 4=Very Much). Using linear transformation, raw scores are standardized, so that scores range from 0 to 100. The change from baseline in cough (EORTC QLQ-LC13 Item 31) score will be presented. A lower score indicates a better outcome. | Baseline and up to approximately 48 weeks | 
| Change in Score from Baseline in Chest Pain (EORTC QLQ-LC13 Item 40) | The EORTC QLQ-LC13 is a lung cancer-specific supplemental questionnaire used in combination with the EORTC QLQ-C30. Participant responses to the question Have you had pain in your chest? are scored on a 4-point scale (1=Not at All to 4=Very Much). Using linear transformation, raw scores are standardized, so that scores range from 0 to 100. The change from baseline in chest pain (EORTC QLQ-LC13 Item 40) score will be presented. A lower score indicates a better outcome. | Baseline and up to approximately 48 weeks | 
| Time to Deterioration (TTD) from Baseline in Global Health Status/QoL Score (EORTC QLQ-C30 Items 29 and 30) | The EORTC QLQ-C30 is a questionnaire to assess the overall health status and quality of life of cancer patients. Participant responses to the questions How would you rate your overall health during the past week? and How would you rate your overall quality of life during the past week? are scored on a 7-point scale (1= Very poor to 7=Excellent). Using linear transformation, raw scores are standardized, so that scores range from 0 to 100. A higher score indicates a better overall health status and quality of life. TTD is defined as the time to first onset of 10 or more (out of 100) deterioration from baseline and confirmed by a second adjacent 10 or more deterioration from baseline. TTD in the score of EORTC QLQ-C30 Items 29 and 30 will be presented. | Up to approximately 48 weeks | 
| TTD from Baseline in Dyspnea Score (EORTC QLQ-C30 Item 8) | The EORTC QLQ-C30 is a 30-item questionnaire to assess the overall quality of life of cancer patients. Participant responses to the question Were you short of breath? will be scored on a 4-point scale (1=Not at All to 4=Very Much). Using linear transformation, raw scores will be standardized, so that scores range from 0 to 100. Higher scores indicates a worse level of dyspnea. TTD is defined as the time to first onset of 10 or more (out of 100) deterioration from baseline and confirmed by a second adjacent 10 or more deterioration from baseline. TTD in the score of EORTC QLQ-C30 Item 8 will be presented. | Up to approximately 48 weeks | 
| TTD from Baseline in Cough (EORTC Quality of Life Questionnaire-Lung Cancer 13 [QLQ-LC13] Item 31) | The EORTC QLQ-LC13 is a lung cancer-specific supplemental questionnaire used in combination with the EORTC QLQ-C30. Participant responses to the question How much did you cough? will be scored on a 4-point scale (1=Not at All to 4=Very Much). Using linear transformation, raw scores are standardized, so that scores range from 0 to 100. Higher scores indicate more frequent coughing and a worse outcome. TTD is defined as the time to first onset of 10 or more (out of 100) deterioration from baseline and confirmed by a second adjacent 10 or more deterioration from baseline. TTD in the score of EORTC QLQ-LC13 Item 31 will be presented. | Up to approximately 48 weeks | 
| Time to Deterioration from Baseline in Chest Pain (EORTC QLQ-LC13 Item 40) | The EORTC QLQ-LC13 is a lung cancer-specific supplemental questionnaire used in combination with the EORTC QLQ-C30. Participant responses to the question Have you had pain in your chest? are scored on a 4-point scale (1=Not at All to 4=Very Much). Using linear transformation, raw scores are standardized, so that scores range from 0 to 100. Higher scores indicate worse level of chest pain. TTD is defined as the time to first onset of 10 or more (out of 100) deterioration from baseline and confirmed by a second adjacent 10 or more deterioration from baseline. TTD in the score of EORTC QLQ-LC13 Item 40 will be presented. | Up to approximately 48 weeks | 
| Number of Participants Who Experience One or More Adverse Events (AEs) | An AE is defined as 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. | Up to approximately 6 years | 
| Number of Participants Who Discontinue Study Treatment Due to an Adverse Event (AE) | An AE is defined as 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. | Up to approximately 4 years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Anaplastic lymphoma kinase (ALK), Antibody-drug conjugate (ADC), Epidermal growth factor receptor (EGFR), Trophoblast cell-surface antigen 2 (TROP2)