A Study of Carboplatin-Paclitaxel/Nab-Paclitaxel Chemotherapy With or Without Pembrolizumab (MK-3475) in Adults With First Line Metastatic Squamous Non-small Cell Lung Cancer (MK-3475-407/KEYNOTE-407)-China Extension Study

• ClinicalTrials.gov Identifier: NCT03875092
• Recruitment Status: Completed
• First Posted: March 14, 2019
• Results First Posted: October 20, 2021
• Last Update Posted: October 6, 2023
• Sponsor: Merck Sharp & Dohme LLC
• Information provided by (Responsible Party): Merck Sharp & Dohme LLC

Study Description

Brief Summary:

In this China extension study, carboplatin and paclitaxel or nano particle albumin-bound paclitaxel (nab-paclitaxel) with or without pembrolizumab (MK-3475, KEYTRUDA®) will be administered to Chinese adults with first line metastatic squamous non-small cell lung cancer (NSCLC).

The primary hypotheses are that treatment with pembrolizumab prolongs: 1) Progression-free Survival (PFS) by Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST 1.1) as assessed by a blinded central imaging vendor compared to placebo, and 2) Overall Survival (OS) in Chinese participants.

After analysis of interim results was conducted, the protocol was amended (Amendment 5) to allow participants the option to discontinue placebo in the control arm and to switch to pembrolizumab in the event of documented progressive disease as assessed by central review.

Condition or disease	Intervention/treatment	Phase
Non-small Cell Lung Cancer	Biological: Pembrolizumab; Drug: Paclitaxel; Drug: Nab-paclitaxel; Drug: Carboplatin; Drug: Saline placebo for pembrolizumab	Phase 3

Detailed Description:

The MK-3475-407-China Extension Study has enrolled a total of 125 participants, of which 15 participants have been also previously enrolled in the MK-3475-407 global study (NCT02775435).

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 125 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Triple (Participant, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: A Randomized, Double-Blind, Phase III Study of Carboplatin-Paclitaxel/Nab-Paclitaxel Chemotherapy With or Without Pembrolizumab (MK-3475) in First Line Metastatic Squamous Non-small Cell Lung Cancer Subjects (KEYNOTE-407)
• Actual Study Start Date: April 21, 2017
• Actual Primary Completion Date: September 30, 2020
• Actual Study Completion Date: September 14, 2023

Arms and Interventions

Arm	Intervention/treatment
Experimental: Pembrolizumab + Chemotherapy; Participants receive pembrolizumab 200 mg by intravenous (IV) infusion prior to chemotherapy on Day 1 of each 21-day cycle for up to 35 cycles PLUS Investigator's choice of paclitaxel (200 mg/m^2 by IV infusion on Day 1 of each 21-day cycle for 4 cycles) or nab-paclitaxel (100 mg/m^2 by IV infusion on Days 1, 8, 15 of each 21-day cycle for 4 cycles) PLUS carboplatin Area Under the Curve (AUC) 6 by IV infusion on Day 1 of each 21-day cycle for 4 cycles.	Biological: Pembrolizumab; IV infusion; Other Names: MK-3475; KEYTRUDA®; Drug: Paclitaxel; IV infusion; Other Name: TAXOL®; Drug: Nab-paclitaxel; IV infusion; Other Name: ABRAXANE®; Drug: Carboplatin; IV infusion Carboplatin dose should not exceed 900 mg.; Other Name: PARAPLATIN®
Active Comparator: Chemotherapy; Participants receive normal saline by IV infusion prior to chemotherapy on Day 1 of each 21-day cycle for up to 35 cycles PLUS Investigator's choice of paclitaxel (200 mg/m^2 by IV infusion on Day 1 of each 21-day cycle for 4 cycles) or nab-paclitaxel (100 mg/m^2 by IV infusion on Days 1, 8, 15 of each 21-day cycle for 4 cycles) PLUS carboplatin AUC 6 by IV infusion on Day 1 of each 21-day cycle for 4 cycles.	Drug: Paclitaxel; IV infusion; Other Name: TAXOL®; Drug: Nab-paclitaxel; IV infusion; Other Name: ABRAXANE®; Drug: Carboplatin; IV infusion Carboplatin dose should not exceed 900 mg.; Other Name: PARAPLATIN®; Drug: Saline placebo for pembrolizumab; IV infusion

Outcome Measures

Primary Outcome Measures :

1. Progression-free Survival (PFS) as Assessed by Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) [ Time Frame: Up to approximately 33 months (Database cutoff date of 30-Sep-2020) ]
   PFS was defined as the time from randomization to the first documented progressive disease (PD) or death due to any cause, whichever occurred first. Per Response Criteria in Solid Tumors version 1.1 (RECIST 1.1), PD was defined as ≥20% increase in the sum of diameters of target lesions. In addition to the relative increase of 20%, the sum must also have demonstrated an absolute increase of ≥5 mm. Note: The appearance of ≥1 new lesions was also considered PD. PFS as assessed by blinded independent central review per RECIST 1.1 is presented. Data are from the product-limit (Kaplan-Meier) method for censored data.
2. Overall Survival (OS) [ Time Frame: Up to approximately 39 months (Database cutoff date of 30-Sep-2020) ]
   OS was defined as the time from randomization to death due to any cause. OS is presented. Data are from the product-limit (Kaplan-Meier) method for censored data.

Secondary Outcome Measures :

1. Objective Response Rate (ORR) as Assessed by Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) [ Time Frame: Up to approximately 33 months (Database cutoff date of 30-Sep-2020) ]
   ORR was defined as the percentage of participants in the analysis population 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 by RECIST 1.1. ORR as assessed by blinded independent central review per RECIST 1.1 is presented.
2. Duration of Response (DOR) as Assessed by Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) [ Time Frame: Up to approximately 30 months (Database cutoff date of 30-Sep-2020) ]
   For participants who demonstrated a confirmed response (Complete Response [CR]: Disappearance of all target lesions or Partial Response [PR]: At least a 30% decrease in the sum of diameters of target lesions) per RECIST 1.1, DOR was defined as the time from first documented evidence of CR or PR until disease progression as assessed by RECIST 1.1 or death. DOR as assessed by blinded independent central review per RECIST 1.1 is presented.
3. Number of Participants Who Experienced an Adverse Event (AE) [ Time Frame: Up to approximately 31 months (Database cutoff date of 30-Sep-2020) ]
   An AE was defined as any untoward medical occurrence in a participant administered study treatment and which did not necessarily have to have a causal relationship with this treatment. The number of participants who experienced an AE is presented. Data are from the product-limit (Kaplan-Meier) method for censored data.
4. Number of Participants Who Discontinued Study Treatment Due to an Adverse Event (AE) [ Time Frame: Up to approximately 29 months (Database cutoff date of 30-Sep-2020) ]
   The number of participants who discontinued study treatment due to an AE is presented.

Eligibility Criteria

• Ages Eligible for Study: 18 Years and older (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

Inclusion Criteria:

• Has a histologically or cytologically confirmed diagnosis of stage IV (M1a or M1b-American Joint Committee on Cancer [AJCC]) squamous NSCLC.
• Has measurable disease based on RECIST 1.1 as determined by the local site investigator/radiology assessment.
• Has not received prior systemic treatment for metastatic NSCLC.
• Has provided tumor tissue from locations not radiated prior to biopsy.
• Has a life expectancy of at least 3 months.
• Has a performance status of 0 or 1 on the Eastern Cooperative Oncology Group (ECOG) Performance Status.
• Has adequate organ function.
• If female of childbearing potential, is willing to use an adequate method of contraception for the course of the study through 180 days after the last dose of study treatment.
• If male with a female partner(s) of child-bearing potential, must agree to use an adequate method of contraception starting with the first dose of study treatment through 95 days after the last dose of study treatment. Males with pregnant partners must agree to use a condom; no additional method of contraception is required for the pregnant partner.

Exclusion Criteria:

• Has non-squamous histology NSCLC.
• Is currently participating and receiving study therapy or has participated in a study of an investigational agent and received study therapy or used an investigational device within 4 weeks prior to administration of pembrolizumab.
• Before the first dose of study drug: a) Has received prior systemic cytotoxic chemotherapy for metastatic disease; b) Has received other targeted or biological antineoplastic therapy (e.g., erlotinib, crizotinib, cetuximab) for metastatic disease; c) Has had major surgery (<3 weeks prior to first dose).
• Received radiation therapy to the lung that is >30 Gray (Gy) within 6 months of the first dose of study treatment.
• Completed palliative radiotherapy within 7 days of the first dose of study treatment.
• Is expected to require any other form of antineoplastic therapy while on study.
• Has received a live-virus vaccination within 30 days of planned treatment start.
• Has a known history of prior malignancy except if the participant has undergone potentially curative therapy with no evidence of that disease recurrence for 5 years since initiation of that therapy.
• Has known active central nervous system (CNS) metastases and/or carcinomatous meningitis.
• Has pre-existing peripheral neuropathy that is ≥ Grade 2 by Common Terminology Criteria for Adverse Events (CTCAE) Version 4 criteria.
• Previously had a severe hypersensitivity reaction to treatment with another monoclonal antibody.
• Has a known sensitivity to any component of carboplatin or paclitaxel or nab-paclitaxel.
• Has active autoimmune disease that has required systemic treatment in past 2 years.
• Is on chronic systemic steroids.
• Had prior treatment with any other anti-programmed cell death 1 (anti-PD-1), or programmed cell death ligand 1 (PD-L1) or PD-L2 agent or an antibody or a small molecule targeting other immuno-regulatory receptors or mechanisms.
• Has participated in any other pembrolizumab trial and has been treated with pembrolizumab.
• Has an active infection requiring therapy.
• Has known history of Human Immunodeficiency Virus (HIV).
• Has known active Hepatitis B virus (HBV) or Hepatitis C virus (HCV) infection.
• Is, at the time of providing documented informed consent, a regular user (including "recreational use") of any illicit drugs or has a recent history (within the last year) of substance abuse (including alcohol).
• Has interstitial lung disease or a history of pneumonitis that required oral or intravenous glucocorticoids to assist with management.

Contacts and Locations

Locations

China

Zhongshan Hospital Fudan University

Shanghai, China, 200032

Sponsors and Collaborators

Merck Sharp & Dohme LLC

Investigators

• Study Director: Medical Director; Merck Sharp & Dohme LLC

  Study Documents (Full-Text)

Documents provided by Merck Sharp & Dohme LLC:

Study Protocol  [PDF] October 30, 2019

Statistical Analysis Plan  [PDF] January 29, 2018

More Information

Additional Information:

Merck Clinical Trials Information 

Publications of Results:

Cheng Y, Zhang L, Hu J, Wang D, Hu C, Zhou J, Wu L, Cao L, Liu J, Zhang H, Sun H, Wang Z, Gao H, Sun Y, Li B, Hu X, Schwarzenberger P, Paz-Ares L. Pembrolizumab Plus Chemotherapy for Chinese Patients With Metastatic Squamous NSCLC in KEYNOTE-407. JTO Clin Res Rep. 2021 Sep 25;2(10):100225. doi: 10.1016/j.jtocrr.2021.100225. eCollection 2021 Oct.

• Responsible Party: Merck Sharp & Dohme LLC
• ClinicalTrials.gov Identifier: NCT03875092
• Other Study ID Numbers: 3475-407 China Extension; 173568 ( Registry Identifier: JAPIC-CTI ); MK-3475-407 ( Other Identifier: Merck Protocol Number ); KEYNOTE-407 ( Other Identifier: Merck )
• First Posted: March 14, 2019
• Results First Posted: October 20, 2021
• Last Update Posted: October 6, 2023
• Last Verified: September 2023

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: Yes
• Plan Description: http://engagezone.msd.com/doc/ProcedureAccessClinicalTrialData.pdf
• URL: http://engagezone.msd.com/ds_documentation.php

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

Keywords provided by Merck Sharp & Dohme LLC:

Programmed Cell Death-1 (PD1, PD-1); Programmed Death-Ligand 1 (PDL1, PD-L1)

Additional relevant MeSH terms:

Lung Neoplasms; Carcinoma, Non-Small-Cell Lung; Respiratory Tract Neoplasms; Thoracic Neoplasms; Neoplasms by Site; Neoplasms; Lung Diseases; Respiratory Tract Diseases; Carcinoma, Bronchogenic; Bronchial Neoplasms; Paclitaxel; Albumin-Bound Paclitaxel; Carboplatin; Pembrolizumab; Antineoplastic Agents, Phytogenic; Antineoplastic Agents; Tubulin Modulators; Antimitotic Agents; Mitosis Modulators; Molecular Mechanisms of Pharmacological Action; Antineoplastic Agents, Immunological; Immune Checkpoint Inhibitors