臨床研究等提出・公開システム

A Phase 3 Randomized, Open-Label, Study of Pembrolizumab (MK-3475) Plus Lenvatinib (E7080/MK-7902) Versus Chemotherapy for First-line Treatment of Advanced or Recurrent Endometrial Carcinoma (LEAP-001)

Phase 3 study of pembrolizumab plus lenvatinib in endometrial carcinoma

842

Lenvatinib + Pembrolizumab group -Mean Age: 62.5 years -Sex: Female 100.0% -Ethnicity: Hispanic or Latino 15.2%, Not Hispanic or Latino 82.6%, Unknown or Not Reported 2.1% -Race: Asian 27.1%, Black or African American 2.4%, White 68.6%, More than one race 1.9% -Eastern Cooperative Oncology Group Performance Status (ECOG PS): [0] 59.5%, [1] 40.5% -Prior Chemotherapy and/or Chemoradiation: Yes 17.6%, No 82.4% -Mismatch repair (MMR) Status: Mismatch repair deficient (dMMR) 23.8%, mismatch repair proficient (pMMR) 76.2% Paclitaxel + Carboplatin group -Mean Age: 64.0 years -Sex: Female 100.0% -Ethnicity: Hispanic or Latino 15.9%, Not Hispanic or Latino 81.3%, Unknown or Not Reported 2.8% -Race: Asian 24.2%, Native Hawaiian or Other Pacific Islander 0.2%, Black or African American 3.3%, White 71.1%, More than one race 1.2% -ECOG PS: [0] 56.9%, [1] 43.1% -Prior Chemotherapy and/or Chemoradiation: Yes 16.1%, No 83.9% -MMR Status: dMMR 23.7%, pMMR 76.3% Total -Mean Age: 63.3 years -Sex: Female 100.0% -Ethnicity: Hispanic or Latino 15.6%, Not Hispanic or Latino 81.9%, Unknown or Not Reported 2.5% -Race: Asian 25.7%, Native Hawaiian or Other Pacific Islander 0.1%, Black or African American 2.9%, White 69.8%, More than one race 1.5% -ECOG PS: [0] 58.2%, [1] 41.8% -Prior Chemotherapy and/or Chemoradiation: Yes 16.9%, No 83.1% -MMR Status: dMMR 23.8%, pMMR 76.2%

Lenvatinib + Pembrolizumab group -Started: 420 participants -Treated: 420 participants -Completed: 0 participants -Not Completed: 420 participants -Reason Not Completed: Ongoing 202 participants, Death 212 participants, Withdrawal by Subject 6 participants Paclitaxel + Carboplatin group -Started: 422 participants -Treated: 411 participants -Completed: 0 participants -Not Completed: 422 participants -Reason Not Completed: Ongoing 186 participants, Death 224 participants, Lost to Follow-up 1 participant, Withdrawal by Subject 11 participants

Percentage of all-cause mortality -Lenvatinib + Pembrolizumab group: 50.71% (213/420 participants) -Paclitaxel + Carboplatin group: 54.03% (228/422 participants) Percentage of participants with serious adverse events -Lenvatinib + Pembrolizumab group: 54.29% (228/420 participants) -Paclitaxel + Carboplatin group: 20.44% (84/411 participants) Serious adverse events with an incidence of >0.95% -Lenvatinib + Pembrolizumab group: Diarrhoea (2.62%), Colitis (2.14%), Urinary tract infection (2.14%), Pneumonitis (2.14%), Hypertension (2.14%), Dehydration (1.67%), Pulmonary embolism (1.67%), Abdominal pain (1.43%), Death (1.43%), Pneumonia (1.43%), Hyponatraemia (1.43%), Anal abscess (1.19%), Cerebrovascular accident (1.19%), Acute kidney injury (1.19%) -Paclitaxel + Carboplatin group: Anaemia (2.19%), Febrile neutropenia (0.97%), Abdominal pain (0.97%), Hyponatraemia (0.97%) Percentage of participants with non-serious adverse events -Lenvatinib + Pembrolizumab group: 99.05% (416/420 participants) -Paclitaxel + Carboplatin group: 96.59% (397/411 participants) Non-serious adverse events with an incidence of >=30% -Lenvatinib + Pembrolizumab group: Hypertension (68.57%), Hypothyroidism (62.38%), Diarrhoea (50.71%), Nausea (37.62%), Proteinuria (34.52%), Fatigue (34.05%), Decreased appetite (34.05%), Arthralgia (31.19%) -Paclitaxel + Carboplatin group: Alopecia (53.53%), Anaemia (50.85%), Nausea (42.09%), Neutrophil count decreased (31.14%), Neutropenia (30.66%)

Primary Outcome Efficacy (pMMR Population) Analysis population: All randomized pMMR participants Progression-free survival (PFS) based on Response Evaluation Criteria In Solid Tumors (RECIST) 1.1 as assessed by blinded independent central review (BICR) -Lenvatinib + Pembrolizumab group: Median 9.6 months [95% confidence interval (CI): 8.2 to 11.9] -Paclitaxel + Carboplatin group: Median 10.2 months (95% CI: 8.4 to 10.4) -Hazard ratio (HR): 1.01 (95% CI: 0.83 to 1.24), P-Value: 0.5550121 Overall survival (OS) -Lenvatinib + Pembrolizumab group: Median 30.9 months (95% CI: 25.4 to 37.7) -Paclitaxel + Carboplatin group: Median 29.4 months (95% CI: 26.2 to 35.4) -[Non-Inferiority] HR: 1.02 (95% CI: 0.83 to 1.26), P-Value: 0.2459875 -[Superiority] HR: 1.02 (95% CI: 0.83 to 1.26), P-Value: 0.5875597 Efficacy (All-comer Population) Analysis population: All randomized participants PFS based on RECIST 1.1 as assessed by BICR -Lenvatinib + Pembrolizumab group: Median 12.5 months (95% CI: 10.3 to 15.1) -Paclitaxel + Carboplatin group: Median 10.2 months (95% CI: 8.4 to 10.4) -HR: 0.92 (95% CI: 0.77 to 1.10), P-Value: 0.1792058 OS -Lenvatinib + Pembrolizumab group: Median 37.7 months (95% CI: 32.2 to 43.6) -Paclitaxel + Carboplatin group: Median 32.1 months (95% CI: 27.2 to 35.7) -[Superiority] HR: 0.93 (95% CI: 0.77 to 1.12), P-Value: 0.21552

Secondary Outcome Additional information including Secondary Outcomes of the study can be found at .

Efficacy The combination of pembrolizumab + lenvatinib did not meet the prespecified statistical criteria for PFS or OS versus chemotherapy as first-line treatment in the participants with Stage III, IV, or recurrent endometrial carcinoma. Safety The observed safety profile for the combination of pembrolizumab + lenvatinib is generally consistent with the known safety profiles of pembrolizumab and lenvatinib monotherapies and with the safety of the combination in other approved indications.

Yes

http://engagezone.msd.com/doc/ProcedureAccessClinicalTrialData.pdf

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

June. 04, 2019

Interventional

randomized controlled trial, parallel assignment, Multicenter, open(masking not used)

treatment purpose

3

1) Have Stage III, Stage IV, or recurrent, histologically-confirmed endometrial carcinoma with disease that is either measurable or non-measurable per RECIST 1.1 but radiographically apparent, as assessed by BICR.
Notes about prior therapy:
- May have received 1 prior line of systemic platinum-based adjuvant and/or neoadjuvant chemotherapy in the setting of a curative-intent resection. This prior chemotherapy may be given as treatment involving chemotherapy alone, concurrent chemoradiation, or as part of a sequential approach such as in a regimen involving concurrent chemoradiation followed by chemotherapy.
- Instances in which both adjuvant and neoadjuvant systemic platinum-based chemotherapy are used will be counted as one line of chemotherapy.
- May have received prior radiation with or without chemotherapy.
- May have received prior hormonal therapy for treatment of endometrial carcinoma, provided that it was discontinued >=1 week prior to randomization.
2) Have provided archival tumor tissue sample or newly obtained core or excisional biopsy of a tumor lesion that was not previously irradiated, for determination of MMR status.
3) Has an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1, as assessed within 7 days prior to the first dose of study intervention
4) A female participant is eligible to participate if she is not pregnant or breastfeeding, and at least one of the following conditions applies:
a. Is not a woman of childbearing potential (WOCBP). OR
b. WOCBP must agree to use contraception as detailed in the study protocol throughout the treatment period and for at least 120 days after the last dose of pembrolizumab or 30 days after the last dose of lenvatinib, whichever is later, and for 180 days after the last dose of chemotherapy.
5) Have adequately controlled BP with or without antihypertensive medications, defined as BP <=150/90 mm Hg with no change in antihypertensive medications within 1 week prior to randomization.
6) Has adequate organ function based on assessment within 7 days prior to the first dose of study intervention

1) Has carcinosarcoma (malignant mixed Mullerian tumor), endometrial leiomyosarcoma or other high grade sarcomas, or endometrial stromal sarcomas.
2) Participants with central nervous system (CNS) metastases are not eligible, unless they have completed local therapy (eg, whole brain radiation therapy [WBRT], surgery or radiosurgery) and have discontinued the use of corticosteroids for this indication for at least 4 weeks before starting treatment in this study. Any signs (eg, radiologic) or symptoms of CNS metastases must be stable for at least 4 weeks before starting study treatment.
3) Has a known additional malignancy (other than endometrial carcinoma) that is progressing or has required active treatment in the last 3 years.
4) Has gastrointestinal malabsorption, or any other condition that might affect the absorption of lenvatinib.
5) Has a pre-existing Grade >=3 gastrointestinal or non-gastrointestinal fistula.
6) Has radiographic evidence of major blood vessel invasion/infiltration.
7) Has active hemoptysis (bright red blood of at least 0.5 teaspoon) within 3 weeks prior to the first dose of study intervention or tumor bleeding within 2 weeks prior to randomization.
8) Has clinically significant cardiovascular disease within 12 months from first dose of study intervention including New York Heart Association Class III or IV congestive heart failure, unstable angina, myocardial infarction, cerebral vascular accident, or cardiac arrhythmia associated with hemodynamic instability.
9) Has an active infection (any infection requiring systemic treatment).
10) Has not recovered adequately from any toxicity and/or complications from major surgery prior to randomization.
11) Has a known history of human immunodeficiency virus (HIV) infection.
12) 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.
13) Has a history of (non-infectious) pneumonitis that required treatment with steroids, or has current pneumonitis.
14) 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.
15) Has a known psychiatric or substance abuse disorder that would interfere with cooperation with the requirements of the study
16) 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 to randomization.
17) Has an active autoimmune disease (with the exception of psoriasis) that has required systemic treatment in the past 2 years (ie, with use of disease modifying agents, corticosteroids or immunosuppressive drugs). Replacement therapy (eg, thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency) is not considered a form of systemic treatment.
18) Has received prior systemic chemotherapy in any setting for the treatment of endometrial carcinoma.
note: prior chemotherapy administered as adjuvant therapy, neoadjuvant therapy, and/or concurrently with radiation is permitted.
19) Has received prior radiotherapy within 4 weeks prior to randomization. Participants must have recovered from all radiation-related toxicities, not require corticosteroids, and not have had radiation pneumonitis. A 2-week washout is permitted for palliative radiation to non-CNS disease and vaginal brachytherapy.
20) Has received prior hormonal therapy for the treatment of endometrial carcinoma within 1 week of randomization.
21) Has received prior therapy with any treatment targeting VEGF-directed angiogenesis, 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 (eg, CTLA-4, OX 40, CD137).
22) Has received a live or live attenuated vaccine within 30 days prior to the first dose of study intervention.
23) Has known intolerance to study intervention (or any of the excipients).
24) Has had an allogenic tissue/solid organ transplant.
25) 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 randomization.
26) Has urine protein >=1 g/24 hours.
Note: Participants with proteinuria >=2+ (>=100 mg/dL) on urine dipstick testing (urinalysis) will undergo 24-hr urine collection for quantitative assessment of proteinuria.
27) Has prolongation of QTcF interval to >480 ms (corrected by Fridericia Formula).
28) Has left ventricular ejection fraction (LVEF) below the institutional normal range as determined by multigated acquisition (MUGA) or echocardiogram (ECHO).

Female

advanced or recurrent endometrial carcinoma

investigational material(s)
Generic name etc : lenvatinib + pembrolizumab
INN of investigational material : lenvatinib, pembrolizumab
Therapeutic category code : 429 Other antitumor agents
Dosage and Administration for Investigational material : Lenvatinib 20 mg Oral QD + Pembrolizumab 200 mg IV Q3W

control material(s)
Generic name etc : paclitaxel + carboplatin
INN of investigational material : paclitaxel, carboplatin
Therapeutic category code : 42- Antineoplastic agents
Dosage and Administration for Investigational material : Paclitaxel 175 mg/m2 IV Q3W + Carboplatin AUC6 IV Q3W

efficacy
- Progression-free survival (PFS) based on Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST 1.1, modified to follow a maximum of 10 target lesions and a maximum of 5 target lesions per organ) as assessed by blinded independent central review (BICR)
- Overall Survival (OS)

safety
efficacy
- Objective Response Rate (ORR) Based on RECIST 1.1 as Assessed by BICR
- European Organization for the Research and Treatment of Cancer (EORTC) QLQ-C30 global health status
- Adverse Event (AE)
- Serious Adverse Event (SAE)
- Immune-Related AE (irAE)
- Study intervention discontinuations due to AEs

April. 23, 2019