Efficacy and Safety Study of Stereotactic Body Radiotherapy (SBRT) With or Without Pembrolizumab (MK-3475) in Adults With Unresected Stage I or II Non-Small Cell Lung Cancer (NSCLC) (MK-3475-867/KEYNOTE-867)

Phase 3TerminatedNCT03924869

Merck Sharp & Dohme LLC448 enrolled

Overview

The purpose of this study is to assess the efficacy and safety of stereotactic body radiotherapy (SBRT) plus pembrolizumab (MK-3475) in the treatment of adult participants with unresected Stage I or II (Stage IIB N0, M0) non-small cell lung cancer (NSCLC). The primary study hypothesis is SBRT plus pembrolizumab prolongs Event-free Survival (EFS) compared to SBRT plus placebo (normal saline solution).

As of protocol amendment 8, the study was stopped due to an interim analysis that did not support the study primary and key secondary endpoints. All study participants stopped ongoing treatment with pembrolizumab/placebo, and must complete end of trial and safety follow-up visits.

Study Type

INTERVENTIONAL

Allocation

RANDOMIZED

Purpose

TREATMENT

Masking

DOUBLE

Enrollment

448

Conditions

Non-Small Cell Lung Cancer

Interventions

Eligibility

Sex: ALLMin age: 18 Years

Medical Language ↔ Plain English

Inclusion Criteria: * Has previously untreated non-small cell lung cancer (NSCLC) diagnosed by histology or cytology and confirmed as Stage I or II (T1 to limited T3, N0, M0) NSCLC (American Joint Committee on Cancer, AJCC) by chest computed tomography (CT) and positron emission tomography (PET) scan. Participants with pericardium invasion, \>2 nodules or 2 nodules that cannot be treated in one field (\>2 cm apart and/or total planned target volume \[PTV\] \>163 cc) and diaphragm elevation suggestive of phrenic nerve invasion are excluded * Cannot undergo thoracic surgery due to existing medical illness(es) as determined by the site's multi-disciplinary tumor board. Medically operable participants who decide to treat with stereotactic body radiotherapy (SBRT) as definitive therapy rather than surgery are also eligible, if patient's unwillingness to undergo surgical resection is clearly documented * Has a Eastern Cooperative Oncology Group (ECOG) Performance Status of 0, 1, or 2 * Is able to receive SBRT and does not have an ultra-centrally located tumor * Has adequate organ function within 7 days prior to the start of study treatment * A female is eligible to participate if she is not pregnant, not breastfeeding, and at least one of the following conditions applies: a) not a women of childbearing potential (WOCBP) OR b) A WOCBP and uses contraceptive method that is highly effective (with a failure rate of \<1% per year), or be abstinent from heterosexual intercourse as their preferred and usual lifestyle (abstinent on a long-term and persistent basis), during the intervention period and for at least 120 days after the last dose of pembrolizumab/placebo and 180 days after the last radiotherapy dose * Male participants are eligible to participate if they agree to the following during the intervention period and for at least 90 days after the last dose of radiotherapy: refrain from donating sperm plus either be abstinent from heterosexual intercourse as their preferred and usual lifestyle (abstinent on a long-term and persistent basis) and agree to remain abstinent or must agree to use contraception per study protocol, unless confirmed to be azoospermic * Has a radiation therapy plan approved by the central radiation therapy quality assurance vendor Exclusion Criteria: * Has received prior therapy with an anti-programmed cell death-1 (anti-PD-1), anti-programmed cell death-ligand 1 (anti-PD-L1), or anti PD-L2 agent or with an agent directed to another stimulatory or co-inhibitory T-cell receptor (e.g. cytotoxic T-lymphocyte-associated antigen 4 \[CTLA-4\], tumor necrosis factor receptor superfamily member 4 \[OX-40\], tumor necrosis factor receptor superfamily member 9 \[CD137\]) * Has received prior radiotherapy to the thorax, including radiotherapy to the esophagus, mediastinum, or breast * Has received a live vaccine within 30 days prior to the first dose of study intervention * Has received an investigational agent or has used an investigational device within 4 weeks prior to the first dose of study intervention administration * Has a diagnosis of immunodeficiency or is receiving chronic systemic steroid therapy (in dosing exceeding 10 mg daily of prednisone equivalent) or any other form of immunosuppressive therapy within 7 days prior the first dose of study treatment * Has a known additional malignancy that is progressing or has required active treatment within the past 3 years. A prior NSCLC that occurred and was treated curatively at least 2 years prior to the date of the current diagnosis would be considered a separate primary lung cancer, and therefore an additional malignancy. Note: Participants with basal cell carcinoma of the skin, squamous cell carcinoma of the skin, or carcinoma in situ (e.g. breast c carcinoma, cervical cancer in situ) that have undergone potentially curative therapy are not excluded. * Has a known hypersensitivity (≥Grade 3) to pembrolizumab and/or any of its excipients * Has a history of (non-infectious) pneumonitis that required steroids or has current pneumonitis * Has a known history of Hepatitis B or known active Hepatitis C virus infection * Has an active autoimmune disease that has required systemic treatment in past 2 years, except replacement therapy * Has an active infection requiring systemic therapy * Has a known history of human immunodeficiency virus (HIV) infection * Has a known history of active tuberculosis (TB; Bacillus tuberculosis) * Is pregnant or breastfeeding or expecting to conceive or father children within the projected duration of the study, starting with the screening visit through 120 days after the last dose of pembrolizumab/placebo and 180 days after the last radiotherapy dose * Have not adequately recovered from major surgery or have ongoing surgical complications * Has had an allogenic tissue/solid organ transplant

Locations (194)

University of Alabama ( Site 0099)

Birmingham, Alabama, United States

Infirmary Cancer Care ( Site 3044)

Mobile, Alabama, United States

Alaska Oncology and Hematology ( Site 3063)

Anchorage, Alaska, United States

Banner MD Anderson Cancer Center ( Site 3029)

Gilbert, Arizona, United States

CARTI Cancer Center ( Site 3045)

Little Rock, Arkansas, United States

Outcomes

Primary Outcomes

Event-free Survival (EFS)

EFS was defined as the time from randomization to the first occurrence of any of the following events: 1) local, regional, or distant recurrence of disease as assessed by radiographic recurrence by blinded independent central review (BICR), positive pathology by local assessment, physical examination by local assessment confirmed by positive pathology and/or radiographic recurrence by BICR, OR 2) death due to any cause. EFS was reported for each arm.

Time frame: Up to approximately 56.8 months

Secondary Outcomes

Overall Survival (OS)

OS was defined as the time from date of randomization to date of death from any cause. OS was reported for each arm.

Time frame: Up to approximately 56.8 months

Time to Death or Distant Metastases (TDDM)

TTDM was defined as the time from randomization to the first documented distant metastases or death from any cause, whichever occurred first. The TDDM was reported for each arm.

Time frame: Up to approximately 56.8 months

Number of Participants Who Experienced an Adverse Event (AE)

An AE was defined as any untoward medical occurrence in a participant, temporally associated with the use of study treatment, whether or not considered related to the study treatment. The number of participants who experienced an AE were reported.

Time frame: Up to approximately 64 months

Number of Participants Who Discontinued Study Treatment Due to an Adverse Event (AE)

Time frame: Up to approximately 16 months

Change From Baseline in European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30 (EORTC QLQ-C30) Global Health Status/Quality of Life (Items 29 and 30) Score

The EORTC QLQ-C30 is a questionnaire to assess the overall 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?" were scored on a 7-point scale (1=Very Poor to 7=Excellent). The combined score of Global Health Status (EORTC QLQ-C30 Item 29) and Quality of Life (EORTC QLQ-C30 Item 30) was computed by averaging the raw scores of the 2 items and then applying a linear transformation to standardize the average score, so that the combined scores ranged from 0-100. A higher score indicates a better outcome. The change from baseline in GHS/QoL combined score was reported for each arm.