A Phase 3, Randomized, Placebo-Controlled Clinical Study to Evaluate the Safety and Efficacy of Stereotactic Body Radiotherapy (SBRT) With or Without Pembrolizumab (MK-3475) in Participants With Unresected Stages I or II Non Small Cell Lung Cancer (NSCLC) (KEYNOTE-867)
Overview
- Phase
- Phase 3
- Intervention
- Stereotactic Body Radiotherapy (SBRT)
- Conditions
- Non-Small Cell Lung Cancer
- Sponsor
- Merck Sharp & Dohme LLC
- Enrollment
- 448
- Locations
- 194
- Primary Endpoint
- Event-free Survival (EFS)
- Status
- Terminated
- Last Updated
- 4 months ago
Overview
Brief Summary
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).
Detailed Description
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.
Investigators
Eligibility Criteria
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
Arms & Interventions
SBRT + Pembrolizumab
Participants receive SBRT once every 3 days for 3, 4, 5, or 8 fractions (dependent on tumor type/location; 45-70 Gray \[Gy\] total) over approximately 2 weeks PLUS pembrolizumab 200 mg via intravenous (IV) infusion once every 3 weeks for up to 17 cycles (up to approximately 1 year). Each cycle is 21 days.
Intervention: Stereotactic Body Radiotherapy (SBRT)
SBRT + Pembrolizumab
Participants receive SBRT once every 3 days for 3, 4, 5, or 8 fractions (dependent on tumor type/location; 45-70 Gray \[Gy\] total) over approximately 2 weeks PLUS pembrolizumab 200 mg via intravenous (IV) infusion once every 3 weeks for up to 17 cycles (up to approximately 1 year). Each cycle is 21 days.
Intervention: Pembrolizumab
SBRT + Placebo
Participants receive SBRT once every 3 days for 3, 4, 5, or 8 fractions (dependent on tumor type/location; 45-70 Gy total) over approximately 2 weeks PLUS placebo (normal saline solution) via IV infusion once every 3 weeks for up to 17 cycles (up to approximately 1 year). Each cycle is 21 days.
Intervention: Stereotactic Body Radiotherapy (SBRT)
SBRT + Placebo
Participants receive SBRT once every 3 days for 3, 4, 5, or 8 fractions (dependent on tumor type/location; 45-70 Gy total) over approximately 2 weeks PLUS placebo (normal saline solution) via IV infusion once every 3 weeks for up to 17 cycles (up to approximately 1 year). Each cycle is 21 days.
Intervention: Placebo
Outcomes
Primary Outcomes
Event-free Survival (EFS)
Time Frame: Up to approximately 56.8 months
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.
Secondary Outcomes
- Overall Survival (OS)(Up to approximately 56.8 months)
- Time to Death or Distant Metastases (TDDM)(Up to approximately 56.8 months)
- Number of Participants Who Experienced an Adverse Event (AE)(Up to approximately 64 months)
- Number of Participants Who Discontinued Study Treatment Due to an Adverse Event (AE)(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(Baseline and up to 24 weeks)
- Change From Baseline in European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-Lung Cancer Module 13 (EORTC QLQ-LC13) Cough (Item 31) Score(Baseline and up to 24 weeks)
- Change From Baseline in European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-Lung Cancer Module 13 (EORTC QLQ-LC13) Chest Pain (Item 40) Score(Baseline and up to 24 weeks)
- Change From Baseline in European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30 (EORTC QLQ-C30) Dyspnea (Item 8) Score(Baseline and up to 24 weeks)
- Change From Baseline in European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-C30 (EORTC QLQ-C30) Physical Functioning (Items 1-5) Score(Baseline and up to 24 weeks)