臨床研究等提出・公開システム

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 Stage I or II Non-Small Cell Lung Cancer (NSCLC) (KEYNOTE-867)

Phase 3 study of SBRT +- pembrolizumab for participants with unresected Stage I or II NSCLC

448

Stereotactic body radiotherapy (SBRT) + Pembrolizumab group -Mean Age: 73.2 years -Sex: Female 39.2%, Male 60.8% -Ethnicity: Hispanic or Latino 10.1%, Not Hispanic or Latino 83.7%, Unknown or Not Reported 6.2% -Race: American Indian or Alaska Native 0.0%, Asian 13.7%, Black or African American 1.8%, White 80.6%, More Than One Race 0.0%, Unknown or Not Reported 4.0% -Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) Score: ECOG PS 0 = Normal activity 37.9%, ECOG PS 1 = Symptoms, but ambulatory 53.7%, ECOG PS 2 = Ambulatory, capable of selfcare, unable to carry out work activities 8.4% -Non-Small Cell Lung Cancer (NSCLC) Disease Stage: Stage I 89.9%, Stage II 10.1% -Geographic Region of Enrollment Site: East Asia 12.8%, Non-East Asia 87.2% -Reason for Not Receiving Surgery: Refused Surgery 18.9%, Medically Inoperable 81.1% SBRT + Placebo group -Mean Age: 72.4 years -Sex: Female 45.2%, Male 54.8% -Ethnicity: Hispanic or Latino 9.0%, Not Hispanic or Latino 84.2%, Unknown or Not Reported 6.8% -Race: American Indian or Alaska Native 0.5%, Asian 11.8%, Black or African American 2.7%, White 80.1%, More Than One Race 0.9%, Unknown or Not Reported 4.1% -ECOG PS Score: ECOG PS 0 = Normal activity 38.0%, ECOG PS 1 = Symptoms, but ambulatory 55.2%, ECOG PS 2 = Ambulatory, capable of selfcare, unable to carry out work activities 6.8% -NSCLC Disease Stage: Stage I 89.1%, Stage II 10.9% -Geographic Region of Enrollment Site: East Asia 11.8%, Non-East Asia 88.2% -Reason for Not Receiving Surgery: Refused Surgery 16.3%, Medically Inoperable 83.7% Total -Mean Age: 72.8 years -Sex: Female 42.2%, Male 57.8% -Ethnicity: Hispanic or Latino 9.6%, Not Hispanic or Latino 83.9%, Unknown or Not Reported 6.5% -Race: American Indian or Alaska Native 0.2%, Asian 12.7%, Black or African American 2.2%, White 80.4%, More Than One Race 0.4%, Unknown or Not Reported 4.0% -ECOG PS Score: ECOG PS 0 = Normal activity 37.9%, ECOG PS 1 = Symptoms, but ambulatory 54.5%, ECOG PS 2 = Ambulatory, capable of selfcare, unable to carry out work activities 7.6% -NSCLC Disease Stage: Stage I 89.5%, Stage II 10.5% -Geographic Region of Enrollment Site: East Asia 12.3%, Non-East Asia 87.7% -Reason for Not Receiving Surgery: Refused Surgery 17.6%, Medically Inoperable 82.4%

SBRT + Pembrolizumab group -Started: 227 participants -Treated: 226 participants -Completed: 0 participants -Not Completed: 227 participants (Death: 73 participants, Lost to Follow-up: 3 participants, Physician Decision: 0 participants, Withdrawal by Subject: 7 participants, Study Terminated by Sponsor: 144 participants) SBRT + Placebo group -Started: 221 participants -Treated: 218 participants -Completed: 0 participants -Not Completed: 221 participants (Death: 62 participants, Lost to Follow-up: 0 participants, Physician Decision: 3 participants, Withdrawal by Subject: 3 participants, Study Terminated by Sponsor: 153 participants)

Percentage of Participants With Serious Adverse Events (SAEs) -SBRT + Pembrolizumab group: 39.82% (90/226 participants) -SBRT + Placebo group: 33.94% (74/218 participants) SAEs With an Incidence of >=1% -SBRT + Pembrolizumab group: Pneumonia (8.41%), Chronic obstructive pulmonary disease (7.08%), Pneumonitis (3.10%), Pneumonia bacterial (2.65%), Urinary tract infection (2.65%), Anaemia (1.77%), Atrial fibrillation (1.77%), Cardiac failure (1.33%), COVID-19 pneumonia (1.33%), Cerebrovascular accident (1.33%), Dyspnoea (1.33%) -SBRT + Placebo group: Chronic obstructive pulmonary disease (4.59%), Pneumonia (3.21%), COVID-19 pneumonia (2.75%), COVID-19 (2.29%), Dyspnoea (1.38%) Percentage of Participants With Nonserious Adverse Events (AEs) With an Incidence of >5% in One or More Treatment Groups -SBRT + Pembrolizumab group: 87.61% (198/226 participants) -SBRT + Placebo group: 80.73% (176/218 participants) Nonserious AEs With an Incidence of >=10% -SBRT + Pembrolizumab group: Fatigue (22.57%), Dyspnoea (18.14%), Arthralgia (17.70%), Pruritus (17.26%), Diarrhoea (16.81%), Hypothyroidism (16.37%), Rash (15.93%), Cough (15.04%), Anaemia (12.39%), Decreased appetite (11.50%) -SBRT + Placebo group: Fatigue (19.72%), Dyspnoea (17.89%), Cough (17.89%), Diarrhoea (14.22%), Nausea (11.47%)

Primary Outcome Efficacy Event-free Survival (EFS) -Analysis Population: all randomized participants -SBRT + Pembrolizumab group: Median 31.2 months [95% confidence interval (CI): 22.5 to 39.1] -SBRT + Placebo group: Median 28.3 months (95% CI: 19.8 to 33.1) -Hazard ratio (HR): 0.92 (95% CI: 0.69 to 1.24), P-Value: 0.29320

Secondary Outcome Efficacy Overall Survival (OS) -Analysis Population: all randomized participants -SBRT + Pembrolizumab group: Median 54.7 months [95% CI: 33.5 to not applicable (NA)] -SBRT + Placebo group: Median NA (95% CI: 44.4 to NA) -HR: 1.33 (95% CI: 0.93 to 1.90), P-Value: 0.93971 Time to Death or Distant Metastases (TDDM) -Analysis Population: all randomized participants -SBRT + Pembrolizumab group: Median 39.1 months (95% CI: 30.5 to NA) -SBRT + Placebo group: Median 41.3 months (95% CI: 31.1 to NA) -HR: 1.02 (95% CI: 0.74 to 1.42) Change From Baseline in European Organisation for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire-Core 30 (QLQ-C30) Global Health Status/Quality of Life (QoL) (Items 29 and 30) Score -Analysis Population: all randomized participants who received at least 1 dose of study intervention and have at least 1 EORTC QLQ-C30 assessment available -SBRT + Pembrolizumab group: Least Square Means -2.17 (95% CI: -5.00 to 0.66) -SBRT + Placebo group: Least Square Means -0.96 (95% CI: -3.78 to 1.86) -Mean Difference (Final Values): -1.21 (95% CI: -4.90 to 2.48), P-Value: 0.5187 Change From Baseline in EORTC Quality of Life Questionnaire-Lung Cancer Module 13 (QLQ-LC13) Cough (Item 31) Score -Analysis Population: all randomized participants who received at least 1 dose of study intervention and have at least 1 EORTC QLQ-LC13 assessment available -SBRT + Pembrolizumab group: Least Squares Mean -1.44 (95% CI: -5.23 to 2.36) -SBRT + Placebo group: Least Squares Mean 2.91 (95% CI: -0.87 to 6.68) -Mean Difference (Final Values): -4.34 (95% CI: -9.38 to 0.69), P-Value: 0.0906 Change From Baseline in EORTC QLQ-LC13 Chest Pain (Item 40) Score -Analysis Population: all randomized participants who received at least 1 dose of study intervention and have at least 1 EORTC QLQ-LC13 assessment available -SBRT + Pembrolizumab group: Least Square Means 3.00 (95% CI: -0.09 to 6.10) -SBRT + Placebo group: Least Square Means 1.76 (95% CI: -1.32 to 4.84) -Mean Difference (Final Values): 1.24 (95% CI: -2.83 to 5.31), P-Value: 0.5482 Change From Baseline in EORTC QLQ-C30 Dyspnea (Item 8) Score -Analysis Population: all randomized participants who received at least 1 dose of study intervention and have at least 1 EORTC QLQ-C30 assessment available -SBRT + Pembrolizumab group: Least Square Means -1.80 (95% CI: -5.95 to 2.36) -SBRT + Placebo group: Least Square Means -0.81 (95% CI: -4.94 to 3.32) -Mean Difference (Final Values): -0.99 (95% CI: -6.50 to 4.53), P-Value: 0.7253 Change From Baseline in EORTC QLQ-C30 Physical Functioning (Items 1-5) Score -Analysis Population: all randomized participants who received at least 1 dose of study intervention and have at least 1 EORTC QLQ-C30 assessment available -SBRT + Pembrolizumab group: Least Square Means -0.52 (95% CI: -3.08 to 2.03) -SBRT + Placebo group: Least Square Means -0.31 (95% CI: -2.86 to 2.24) -Mean Difference (Final Values): -0.21 (95% CI: -3.70 to 3.28), P-Value: 0.9055 Safety Number of Participants Who Experienced an AE -Analysis Population: all participants who received at least 1 dose of study treatment -SBRT + Pembrolizumab group: 217 participants (96.0%) -SBRT + Placebo group: 200 participants (91.7%) Number of Participants Who Discontinued Study Treatment Due to an AE -Analysis Population: all participants who received at least 1 dose of study treatment -SBRT + Pembrolizumab group: 62 participants (27.4%) -SBRT + Placebo group: 25 participants (11.5%)

Efficacy and Patient-Reported Outcomes SBRT + Pembrolizumab did not provide statistically significant or clinically meaningful improvement in EFS when compared with SBRT alone. Deterioration in HRQoL was observed in both SBRT + Pembrolizumab and SBRT + Placebo groups. Safety SBRT + Pembrolizumab increased frequency and severity of AEs. This is consistent with the established safety profile of the individual treatments and the underlying disease. No new safety concerns were identified for pembrolizumab.

Sept. 19, 2024

https://pubmed.ncbi.nlm.nih.gov/39298144/

Yes

https://engagezone.msd.com/

Fujita Tomoko

MSD K.K.

KITANOMARU SQUARE,1-13-12,Kudan-kita,Chiyoda-ku,Tokyo 102-8667,Japan

JPCT@msd.com

MSDJRCT inquiry mailbox

MSD K.K.

KITANOMARU SQUARE,1-13-12,Kudan-kita,Chiyoda-ku,Tokyo 102-8667,Japan

+81-3-6272-1957

JPCT@msd.com

completed

May. 02, 2020

Interventional

randomized controlled trial,double blind,placebo control,parallel assignment

treatment purpose

3

1)Has previously untreated NSCLC diagnosed by histology or cytology and confirmed as Stage I or II (T1 to limited T3, N0, M0) NSCLC (AJCC 8th edition) by chest CT and PET scan
2)Cannot undergo thoracic surgery due to existing medical illness(es) or anatomically unresectable tumor as determined by the
site's multidisciplinary tumor board. Medically operable participants who decide to treat with SBRT as definitive therapy rather than surgery are also eligible, if patient's unwillingness to undergo surgical resection is clearly documented
3)Has a ECOG Performance Status of 0, 1, or 2
4)Is able to receive SBRT and does not have an ultra-centrally located tumor
5)Has adequate organ function
6)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
7)Has a radiation therapy plan approved by the central radiation therapy quality assurance vendor

1)Has received prior therapy with an anti-PD-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. CTLA-4, OX-40, CD137)
2)Has received prior radiotherapy to the thorax, including radiotherapy to the esophagus, mediastinum, or breast.Participants receiving radiotherapy to the contralateral breast at least 5 years prior to randomization may still be eligible
3)Has received a live vaccine within 30 days prior to the first dose of study intervention
4)Has received an investigational agent or has used an investigational device within 4 weeks prior to the first dose of study intervention administration
5)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
6)Has a known additional malignancy that is progressing or has required active treatment within the past 3 years.Participants with basal cell carcinoma of the skin, squamous cell carcinoma of the skin, or carcinoma in situ (e.g. breast carcinoma, cervical cancer in situ) that have undergone potentially curative therapy are not excluded
7)Has a known hypersensitivity (>=Grade 3) to pembrolizumab and/or any of its excipients
8)Has a history of (non-infectious) pneumonitis that required steroids or has current pneumonitis
9)Has a known history of hepatitis B (defined as hepatitis B surface antigen [HBsAg] reactive) or known active hepatitis C virus (defined as HCV RNA [qualitative] is detected) infection.No testing for hepatitis B and hepatitis C is required unless mandated by local health authority
Note: No testing for hepatitis B and hepatitis C is required unless mandated by local
health authority
10)Has an active autoimmune disease that has required systemic treatment in past 2 years, except replacement therapy
11)Has an active infection requiring systemic therapy
12)Has a known history of human immunodeficiency virus (HIV) infection
13)Has a known history of active tuberculosis (TB; Bacillus tuberculosis)
14)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
15)Has had an allogeneic tissue/solid organ transplant

Both

Non-Small Cell Lung Cancer

investigational material(s)
Generic name etc: SBRT; + MK-3475
INN of investigational material: pembrolizumab
Therapeutic category code: 429 Other antitumor agents
Dosage and Administration for Investigational material:
- SBRT, every 3 days(Q3D), 3-5 fractions(depending on tumor site), over 2 weeks
- pembrolizumab 200 mg, every 3 weeks(Q3W) IV Infusion, x17 cycles(1 year)

control material(s)
Generic name etc: SBRT+ placebo
INN of investigational material: -
Therapeutic category code: Other
Dosage and Administration for Investigational material:
- SBRT, Q3D, 3-5 fractions(depending on tumor site), over 2 weeks
- placebo, Q3W IV Infusion, x17 cycles(1 year)

efficacy
- the Event-free Survival (EFS) : The time from randomization to an event defined as local, regional, or distant recurrence of the treated NSCLC or death from any cause.

- Overall Survival(OS) : The time from randomization to death from any cause.
- Time to death or distant metastases(TDDM) : The time from randomization to the first documented distant metastases or death from any cause, whichever occurs first.
- safety and efficacy : Adverse events, Study intervention discontinuations due to AEs
- global health status/quality of life(QoL) (European Organization for Research and Treatment of Cancer [EORTC] Quality of Life Questionnaire-Core 30 items [QLQ-C30 Items] 29 and 30), cough (EORTC Quality of Life Questionnaire-Lung Cancer Module 13 [QLQ-LC13] Item 1), chest pain (EORTC QLQ-LC13 Item 10), dyspnea (EORTC QLQ-C30 Item 8), and physical functioning (EORTC QLQ-C30 Items 1-5).

+81-3-3520-0111

Sept. 04, 2019