臨床研究等提出・公開システム

A Phase 2 Precision Oncology Study of Biomarker-Directed, Pembrolizumab- (MK-3475, SCH 900475) Based Combination Therapy for Advanced Non-Small Cell Lung Cancer (KEYNOTE-495; KeyImPaCT)

KeyImPaCT: Keytruda Immunotherapy Personalized and Combination Treatment

245

Pembrolizumab + Lenvatinib group -Mean Age: 65.4 years -Sex: Female 38.3%, Male 61.7% -Ethnicity: Hispanic or Latino 2.5%, Not Hispanic or Latino 93.8%, Unknown or Not Reported 3.7% -Race: American Indian or Alaska Native 0.0%, Asian 27.2%, Black or African American 1.2%, White 69.1%, Unknown or Not Reported 2.5% -Biomarker Defined Subgroups: Gene expression profile (GEP) Low/tumor mutational burden (TMB) Low 30.9%, GEP Low/TMB High 16.0%, GEP High/TMB Low 27.2%, GEP High/TMB High 25.9% Pembrolizumab + Quavonlimab group -Mean Age: 67.3 years -Sex: Female 36.1%, Male 63.9% -Ethnicity: Hispanic or Latino 2.4%, Not Hispanic or Latino 95.2%, Unknown or Not Reported 2.4% -Race: American Indian or Alaska Native 1.2%, Asian 30.1%, Black or African American 3.6%, White 62.7%, Unknown or Not Reported 2.4% -Biomarker Defined Subgroups: GEP Low/TMB Low 31.3%, GEP Low/TMB High 15.7%, GEP High/TMB Low 26.5%, GEP High/TMB High 26.5% Pembrolizumab + Favezelimab 200 mg group -Mean Age: 62.4 years -Sex: Female 30.0%, Male 70.0% -Ethnicity: Hispanic or Latino 10.0%, Not Hispanic or Latino 90.0%, Unknown or Not Reported 0.0% -Race: American Indian or Alaska Native 0.0%, Asian 26.7%, Black or African American 0.0%, White 70.0%, Unknown or Not Reported 3.3% -Biomarker Defined Subgroups: GEP Low/TMB Low 36.7%, GEP Low/TMB High 20.0%, GEP High/TMB Low 26.7%, GEP High/TMB High 16.7% Pembrolizumab + Favezelimab 800 mg group -Mean Age: 67.9 years -Sex: Female 29.4%, Male 70.6% -Ethnicity: Hispanic or Latino 0.0%, Not Hispanic or Latino 94.1%, Unknown or Not Reported 5.9% -Race: American Indian or Alaska Native 0.0%, Asian 37.3%, Black or African American 0.0%, White 60.8%, Unknown or Not Reported 2.0% -Biomarker Defined Subgroups: GEP Low/TMB Low 0.0%, GEP Low/TMB High 21.6%, GEP High/TMB Low 43.1%, GEP High/TMB High 35.3% Total -Mean Age: 66.2 years -Sex: Female 34.7%, Male 65.3% -Ethnicity: Hispanic or Latino 2.9%, Not Hispanic or Latino 93.9%, Unknown or Not Reported 3.3% -Race: American Indian or Alaska Native 0.4%, Asian 30.2%, Black or African American 1.6%, White 65.3%, Unknown or Not Reported 2.4% -Biomarker Defined Subgroups: GEP Low/TMB Low 25.3%, GEP Low/TMB High 17.6%, GEP High/TMB Low 30.2%, GEP High/TMB High 26.9%

Pembrolizumab + Lenvatinib group -Started: 81 participants -Treated: 80 participants -Completed: 0 participants -Not Completed: 81 participants -Reason Not Completed: Withdrawal by Subject 2 participants, Sponsor Decision 9 participants, Randomized by Mistake Without Study Treatment 1 participant, Lost to Follow-up 0 participants, Death 69 participants Pembrolizumab + Quavonlimab group -Started: 83 participants -Treated: 82 participants -Completed: 0 participants -Not Completed: 83 participants -Reason Not Completed: Withdrawal by Subject 5 participants, Sponsor Decision 16 participants, Randomized by Mistake Without Study Treatment 1 participant, Lost to Follow-up 0 participants, Death 61 participants Pembrolizumab + Favezelimab 200 mg group -Started: 30 participants -Treated: 30 participants -Completed: 0 participants -Not Completed: 30 participants -Reason Not Completed: Withdrawal by Subject 0 participants, Sponsor Decision 5 participants, Randomized by Mistake Without Study Treatment 0 participants, Lost to Follow-up 0 participants, Death 25 participants Pembrolizumab + Favezelimab 800 mg group -Started: 51 participants -Treated: 51 participants -Completed: 0 participants -Not Completed: 51 participants -Reason Not Completed: Withdrawal by Subject 3 participants, Sponsor Decision 12 participants, Randomized by Mistake Without Study Treatment 0 participants, Lost to Follow-up 2 participants, Death 34 participants

Percentage of Participants With Serious Adverse Events (SAEs) -Pembrolizumab + Lenvatinib group: 52.50% (42/80 participants) -Pembrolizumab + Quavonlimab group: 47.56% (39/82 participants) -Pembrolizumab + Favezelimab 200 mg group: 46.67% (14/30 participants) -Pembrolizumab + Favezelimab 800 mg group: 60.78% (31/51 participants) SAEs With an Incidence of >=3.5% -Pembrolizumab + Lenvatinib group: Pneumonia (7.5%), Myocardial infarction (6.25%), Diarrhoea (3.75%), COVID-19 pneumonia (3.75%), Urinary tract infection (3.75%) -Pembrolizumab + Quavonlimab group: Pneumonia (7.32%), Pleural effusion (3.66%), COVID-19 (3.66%) -Pembrolizumab + Favezelimab 200 mg group: Pneumonia (6.67%), Ischaemic stroke (6.67%) -Pembrolizumab + Favezelimab 800 mg group: Pneumonia (7.84%), Pleural effusion (5.88%), Pneumonitis (5.88%), Pericardial effusion (5.88%), COVID-19 (5.88%), COVID-19 pneumonia (3.92%), Hyponatraemia (3.92%) Percentage of Participants With Nonserious Adverse Events (AEs) With an Incidence of >5% in One or More Treatment Groups -Pembrolizumab + Lenvatinib group: 95.00% (76/80 participants) -Pembrolizumab + Quavonlimab group: 91.46% (75/82 participants) -Pembrolizumab + Favezelimab 200 mg group: 83.33% (25/30 participants) -Pembrolizumab + Favezelimab 800 mg group: 92.16% (47/51 participants) Nonserious AEs With an Incidence of >=20% -Pembrolizumab + Lenvatinib group: Hypertension (52.5%), Diarrhoea (45%), Hypothyroidism (36.25%), Decreased appetite (33.75%), Asthenia (32.5%), Fatigue (32.5%), Constipation (28.75%), Nausea (27.5%), Stomatitis (27.5%), Weight decreased (26.25%), Proteinuria (26.25%), Vomiting (25%), Headache (21.25%), Dysphonia (21.25%) -Pembrolizumab + Quavonlimab group: Pruritus (29.27%), Cough (21.95%), Fatigue (20.73%) -Pembrolizumab + Favezelimab 200 mg group: Pyrexia (23.33%), Decreased appetite (20%), Constipation (20%), Pruritus (20%) -Pembrolizumab + Favezelimab 800 mg group: Diarrhoea (29.41%), Fatigue (21.57%)

Primary Outcome Efficacy Objective Response Rate (ORR) (%) -Analysis population: All allocated participants who have received study treatment -Pembrolizumab + Lenvatinib group - GEP Low/TMB Low: 12.0 [95% confidence interval (CI): 2.5, 31.2] -Pembrolizumab + Lenvatinib group - GEP Low/TMB High: 33.3 (95% CI: 9.9, 65.1) -Pembrolizumab + Lenvatinib group - GEP High/TMB Low: 40.9 (95% CI: 20.7, 63.6) -Pembrolizumab + Lenvatinib group - GEP High/TMB High: 57.1 (95% CI: 34.0, 78.2) -Pembrolizumab + Quavonlimab group - GEP Low/TMB Low: 11.5 (95% CI: 2.4, 30.2) -Pembrolizumab + Quavonlimab group - GEP Low/TMB High: 30.8 (95% CI: 9.1, 61.4) -Pembrolizumab + Quavonlimab group - GEP High/TMB Low: 13.6 (95% CI: 2.9, 34.9) -Pembrolizumab + Quavonlimab group - GEP High/TMB High: 52.4 (95% CI: 29.8, 74.3) -Pembrolizumab + Favezelimab 200 mg group - GEP Low/TMB Low: 0.0 (95% CI: 0.0, 28.5) -Pembrolizumab + Favezelimab 200 mg group - GEP Low/TMB High: 33.3 (95% CI: 4.3, 77.7) -Pembrolizumab + Favezelimab 200 mg group - GEP High/TMB Low: 25.0 (95% CI: 3.2, 65.1) -Pembrolizumab + Favezelimab 200 mg group - GEP High/TMB High: 60.0 (95% CI: 14.7, 94.7) -Pembrolizumab + Favezelimab 800 mg group - GEP Low/TMB High: 27.3 (95% CI: 6.0, 61.0) -Pembrolizumab + Favezelimab 800 mg group - GEP High/TMB Low: 13.6 (95% CI: 2.9, 34.9) -Pembrolizumab + Favezelimab 800 mg group - GEP High/TMB High: 50.0 (95% CI: 26.0, 74.0)

Secondary Outcome Efficacy Progression Free Survival (PFS) (months) -Analysis population: All allocated participants who have received study treatment -Pembrolizumab + Lenvatinib group - GEP Low/TMB Low: 5.4 (95% CI: 2.3, 8.8) -Pembrolizumab + Lenvatinib group - GEP Low/TMB High: 13.8 (95% CI: 1.5, 19.4) -Pembrolizumab + Lenvatinib group - GEP High/TMB Low: 8.2 (95% CI: 4.2, 19.7) -Pembrolizumab + Lenvatinib group - GEP High/TMB High: 17.8 (95% CI: 6.0, 20.7) -Pembrolizumab + Quavonlimab group - GEP Low/TMB Low: 2.8 (95% CI: 2.0, 6.0) -Pembrolizumab + Quavonlimab group - GEP Low/TMB High: 3.9 (95% CI: 1.9, 17.3) -Pembrolizumab + Quavonlimab group - GEP High/TMB Low: 6.1 (95% CI: 2.1, 12.8) -Pembrolizumab + Quavonlimab group - GEP High/TMB High: 17.0 (95% CI: 9.3, 29.1) -Pembrolizumab + Favezelimab 200 mg group - GEP Low/TMB Low: 2.1 (95% CI: 1.9, 2.1) -Pembrolizumab + Favezelimab 200 mg group - GEP Low/TMB High: 8.1 [95% CI: 1.7, not applicable (NA)] -Pembrolizumab + Favezelimab 200 mg group - GEP High/TMB Low: 2.1 (95% CI: 0.9, 6.5) -Pembrolizumab + Favezelimab 200 mg group - GEP High/TMB High: 6.3 (95% CI: 0.4, NA) -Pembrolizumab + Favezelimab 800 mg group - GEP Low/TMB High: 4.2 (95% CI: 1.8, 12.2) -Pembrolizumab + Favezelimab 800 mg group - GEP High/TMB Low: 3.5 (95% CI: 2.0, 8.2) -Pembrolizumab + Favezelimab 800 mg group - GEP High/TMB High: 20.2 (95% CI: 6.1, NA) Overall survival (OS) (months) -Analysis population: All allocated participants who have received study treatment -Pembrolizumab + Lenvatinib group - GEP Low/TMB Low: 16.0 (95% CI: 5.4, 20.2) -Pembrolizumab + Lenvatinib group - GEP Low/TMB High: 16.9 (95% CI: 3.8, 33.2) -Pembrolizumab + Lenvatinib group - GEP High/TMB Low: 22.5 (95% CI: 12.0, 41.3) -Pembrolizumab + Lenvatinib group - GEP High/TMB High: 22.7 (95% CI: 16.9, 56.0) -Pembrolizumab + Quavonlimab group - GEP Low/TMB Low: 13.3 (95% CI: 8.4, 20.0) -Pembrolizumab + Quavonlimab group - GEP Low/TMB High: 20.1 (95% CI: 7.7, NA) -Pembrolizumab + Quavonlimab group - GEP High/TMB Low: 23.7 (95% CI: 7.9, 43.1) -Pembrolizumab + Quavonlimab group - GEP High/TMB High: 51.6 (95% CI: 17.6, NA) -Pembrolizumab + Favezelimab 200 mg group - GEP Low/TMB Low: 8.6 (95% CI: 3.8, 35.4) -Pembrolizumab + Favezelimab 200 mg group - GEP Low/TMB High: 20.8 (95% CI: 1.7, NA) -Pembrolizumab + Favezelimab 200 mg group - GEP High/TMB Low: 12.6 (95% CI: 0.9, 25.4) -Pembrolizumab + Favezelimab 200 mg group - GEP High/TMB High: NA (95% CI: 13.5, NA) -Pembrolizumab + Favezelimab 800 mg group - GEP Low/TMB High: 18.6 (95% CI: 3.4, 41.2) -Pembrolizumab + Favezelimab 800 mg group - GEP High/TMB Low: 11.1 (95% CI: 5.2, 19.6) -Pembrolizumab + Favezelimab 800 mg group - GEP High/TMB High: NA (95% CI: 13.0, NA) Safety Number of Participants Experiencing AEs -Analysis population: All allocated participants who have received study treatment -Pembrolizumab + Lenvatinib group: 98.8% (79/80 participants) -Pembrolizumab + Quavonlimab group: 95.1% (78/82 participants) -Pembrolizumab + Favezelimab 200 mg group: 90.0% (27/30 participants) -Pembrolizumab + Favezelimab 800 mg group: 96.1% (49/51 participants) Number of Participants Discontinuing Study Drug Due to AEs -Analysis population: All allocated participants who have received study treatment -Pembrolizumab + Lenvatinib group: 42.5% (34/80 participants) -Pembrolizumab + Quavonlimab group: 22.0% (18/82 participants) -Pembrolizumab + Favezelimab 200 mg group: 13.3% (4/30 participants) -Pembrolizumab + Favezelimab 800 mg group: 29.4% (15/51 participants)

The Pembrolizumab + Lenvatinib group - GEP High/TMB Low met the primary hypothesis (the true ORR exceeded 20%) but other biomarker/treatment combination did not. PFS and OS outcomes are generally consistent with the anticipated results among biomarker-defined cohorts within the participant population. Safety results were generally consistent with the safety profiles of pembrolizumab monotherapy, pembrolizumab in combination, quavonlimab and favezelimab. No new safety concerns were identified.

July. 29, 2023

https://pubmed.ncbi.nlm.nih.gov/37429923/

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

Feb. 13, 2019

Interventional

Group-sequential, Adaptive randomization, multi-site, open-label

treatment purpose

2

1) Has a histologically- or cytologically-confirmed diagnosis of Stage IV (American Joint Committee on Cancer [AJCC] v 8) NSCLC and has not had prior systemic therapy for advanced disease
2) Has confirmation that epidermal growth factor receptor- (EGFR-), anaplastic lymphoma kinase- (ALK-), c-ros oncogene 1- (ROS1-), or B isoform of rapidly accelerated fibrosarcoma- (B-Raf-) directed therapy is not indicated as primary therapy (documentation of absence of tumor activating EGFR mutations, B-Raf mutations, ALK gene rearrangements, and ROS1 gene rearrangements)
3) Has measurable disease per RECIST 1.1 as assessed by the local site investigator/radiology
4) Male participants must agree to use contraception during the treatment period and for >=120 days, after the last dose of study treatment and refrain from donating sperm during this period. Male participants with pregnant partners must agree to use a condom
5) Female participants eligible to participate if not pregnant, not breastfeeding, and not a woman of childbearing potential (WOCBP) or is a WOCBP who agrees to follow contraceptive guidance during the treatment period and for >=120 days after the last dose of study treatment
6) Provided archival tumor tissue sample or newly obtained core or excisional biopsy of a tumor lesion not previously irradiated
7) Has an Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 1
8) Has adequate organ function

1) Has significant cardiovascular impairment within 12 months of the first dose of study drug: history of congestive heart failure greater than New York Heart Association (NYHA) Class II, unstable angina, myocardial infarction or cerebrovascular accident (CVA) stroke, or cardiac arrhythmia associated with hemodynamic instability, significant cardiovascular impairment, or a left ventricular ejection fraction (LVEF) below the institutional normal range as determined by multigated acquisition scan (MUGA) or echocardiogram
2) Prolongation of QTc interval to >480 milliseconds (ms)
3) Has symptomatic ascites or pleural effusion
4) Has had an allogenic tissue/solid organ transplant
5) WOCBP who has a positive urine pregnancy test within 24 hours before the first dose of study treatment
6) Has not recovered adequately from any toxicity and/or complications from major surgery prior to starting therapy, or has had major surgery within 3 weeks prior to first dose of study intervention
7) Has preexisting gastrointestinal or non-gastrointestinal fistula, gastrointestinal malabsorption, gastrointestinal anastomosis, or any other condition that might affect the absorption of lenvatinib
8) Radiographic evidence of major blood vessel invasion/infiltration
9) Clinically significant hemoptysis or tumor bleeding within 2 weeks prior to the first dose of study drug
10) Has received prior systemic chemotherapy treatment for metastatic/recurrent NSCLC
11) Has current NSCLC disease that can be treated with curative intent with surgical resection, localized radiotherapy, or chemoradiation
12) Is expected to require any other form of systemic or localized antineoplastic therapy while on study (including maintenance therapy with another agent for NSCLC, radiation therapy, and/or surgical resection)
13) 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
14) Has received previous treatment with another agent targeting the Lymphocyte-activation gene 3 (LAG-3) receptor
15) Has received previous treatment with another agent targeting vascular endothelial growth factor (VEGF) or the VEGF receptor
16) Has received prior anticancer therapy including investigational agents within 4 weeks prior to randomization
17) Has received prior radiotherapy within 2 weeks of start of study treatment or received lung radiation therapy of >30 Gy within 6 months prior to the first dose of study intervention
18) Has received a live or live-attenuated vaccine within 30 days before the first dose of study treatment
19) Is currently participating in or has participated in a study of an investigational agent or has used an investigational device within 4 weeks prior to the first dose of study treatment.
20) 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
21) Has a known additional malignancy that is progressing or has required active treatment within the past 3 years
22) Has known active central nervous system (CNS) metastases and/or carcinomatous meningitis
23) Has severe hypersensitivity (>=Grade 3) to pembrolizumab, favezelimab, or lenvatinib and/or any of its excipients
24) Has an active autoimmune disease that has required systemic treatment in past 2 years (i.e., with use of disease modifying agents, corticosteroids, or immunosuppressive drugs)
25) Has a history of (noninfectious) pneumonitis that required steroids or has current pneumonitis
26) Has an active infection requiring systemic therapy
27) Has a known history of human immunodeficiency virus (HIV) infection
28) 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
29) Has a known history of active tuberculosis (TB; Bacillus tuberculosis)
30) Has a history or current evidence of any condition, therapy, or laboratory abnormality that might confound the results of the study, interfere with the participant's participation for the full duration of the study, or is not in the best interest of the participant to participate, in the opinion of the treating investigator
31) Has known psychiatric or substance abuse disorders that would interfere with cooperating with the requirements of the study

Both

Advanced Non-Small Cell Lung Cancer

investigational material(s)
Generic name etc : pembrolizumab+MK-4280, pembrolizumab+lenvatinib, pembrolizumab+MK1308
INN of investigational material : pembrolizumab, MK-4280, lenvatinib, MK-1308
Therapeutic category code : 42- Antineoplastic agents
Dosage and Administration for Investigational material : Pembrolizumab 200 mg every 3 weeks (Q3W) + MK-1308 25 mg every 6 weeks (Q6W), Pembrolizumab 200 mg Q3W + MK 4280 either 200 or 800 mg Q3W , Pembrolizumab 200 mg Q3W + lenvatinib 20 mg once daily

control material(s)
Generic name etc :
INN of investigational material : -
Therapeutic category code :
Dosage and Administration for Investigational material :

efficacy
- objective response rate (ORR): Participants who have a confirmed complete response (CR) or partial response (PR) per Response Evaluation Criteria in Solid Tumors 1.1 (RECIST 1.1) as assessed by local site.

safety
efficacy
- PFS: Time from randomization to the first documented disease progression per RECIST 1.1 as assessed by local site or death, whichever occurs first.
- OS: Time from randomization to death due to any cause.
- Number of Participants Experiencing Adverse Events (AEs).
- Number of Participants Discontinuing Study Drug due to AEs.

Dec. 17, 2018