A Trial of Pembrolizumab in Combination With Chemotherapy and Radiotherapy in Stage III NSCLC (KEYNOTE-799, MK-3475-799)

Merck Sharp & Dohme (MSD)

Status and phase: Completed; Phase 2

Conditions: Non-small Cell Lung Cancer

Treatments: Radiation: Thoracic Radiation Therapy (TRT); Drug: Paclitaxel 45 mg/m^2; Drug: Pembrolizumab 200 mg; Drug: Cisplatin 75 mg/m^2; Drug: Pemetrexed 500 mg/m^2; Drug: Carboplatin AUC2; Drug: Paclitaxel 200 mg/m^2; Drug: Carboplatin AUC6

Study type: Interventional

Funder types: Industry

Identifiers

NCT03631784

MK-3475-799 (Other Identifier)

3475-799

2018-000714-37 (EudraCT Number)

Details and patient eligibility

About

This is a trial in adult participants with unresectable, locally advanced, Stage III non-small cell lung cancer (NSCLC) treated with pembrolizumab in combination with platinum doublet chemotherapy and standard thoracic radiotherapy followed by pembrolizumab monotherapy. The primary hypothesis of the trial is that within each platinum doublet chemotherapy cohort, the percentage of participants who develop Grade 3 or higher pneumonitis is ≤10% and estimation of objective response rate (ORR) by blinded independent central review (BICR).

Enrollment: 216 patients

Sex: All

Ages: 18+ years old

Volunteers: No Healthy Volunteers

Inclusion criteria

• Male/female participants, who are at least 18 years of age on the day of signing informed consent with previously untreated, unresectable, pathologically confirmed NSCLC and Stage IIIA, IIIB or IIIC NSCLC by American Joint Committee on Cancer Version 8.
• No evidence of metastatic disease by whole body positron emission tomography/computed tomography (PET/ CT) scan, diagnostic quality CT scan, and brain imaging.
• Have measurable disease per RECIST 1.1 as assessed by the local site investigator/radiology.
• Have provided tumor tissue sample (core, incisional, or excisional biopsy).
• Have an Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 or 1.
• Have adequate pulmonary function test (PFT)
• Have adequate organ function
• A male participant must agree to use contraception through the end of treatment and refrain from donating sperm during this period.
• A female participant is eligible to participate if she is not pregnant, not breastfeeding, and if participant is a woman of childbearing potential (WOCBP), agrees to follow the contraceptive guidance as provided in the protocol through the end of treatment.

Exclusion criteria

• A WOCBP who has a positive urine pregnancy test within 72 hours prior to treatment allocation
• Has small cell lung cancer.
• Has had documented weight loss >10% in the preceding 3 months.
• Participants whose radiation treatment plans are likely to encompass a volume of whole lung receiving >20 Gy in total (V20) of more than 31% of lung volume.
• Has received prior radiotherapy to the thorax, including radiotherapy to the esophagus or for breast cancer.
• Has received prior therapy with an anti-PD-1, anti-PD-L1, or anti-PD-L2 agent (programmed cell death protein 1 [PD-1] and its ligands, programmed cell death ligand 1 (PD-L1) and programmed cell death ligand 2 [PD-L2]) or with an agent directed to another stimulatory or co-inhibitory T-cell receptor (eg, CTLA-4, OX-40, CD137).
• Has received a live vaccine within 30 days prior to the first dose of study drug.
• Has had an allogenic tissue/solid organ transplant.
• 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.
• Has a diagnosis of immunodeficiency or is receiving chronic systemic steroid therapy (in dosing exceeding 10 mg prednisone daily or equivalent) or any other form of immunosuppressive therapy within 7 days prior the first dose of study drug.
• Has a known additional malignancy that is progressing or has required active treatment within the past 5 years.
• Has severe hypersensitivity (Grade 3 or higher) to pembrolizumab and/or any of its excipients.
• Has a known severe hypersensitivity (Grade 3 or higher) to any of the study chemotherapy agents and/or to any of their excipients.
• Has an active autoimmune disease that has required systemic treatment in past 2 years (ie, with use of disease modifying agents, corticosteroids or immunosuppressive drugs).
• Has a history of (non-infectious) pneumonitis/interstitial lung disease that required steroids or has current pneumonitis/interstitial lung disease that requires steroids.
• Has an active infection requiring systemic therapy.
• Has a known history of human immunodeficiency virus (HIV) infection. HIV testing is not required unless mandated by local health authority.
• 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.
• Has a known history of active tuberculosis (TB; Bacillus tuberculosis).
• 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.
• Has a known psychiatric or substance abuse disorder that would interfere with cooperating with the requirements of the study.
• Is pregnant or breastfeeding or expecting to conceive or father children within the projected duration of the study through the end of treatment.

Trial design

Primary purpose: Treatment

Allocation: Randomized

Interventional model: Parallel Assignment

Masking: Double Blind

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216 participants in 2 patient groups

Cohort A

Experimental group

Description:

Participants received 1 cycle of carboplatin area under the curve (AUC) 6 mg/mL/min with paclitaxel 200 mg/m\^2 and pembrolizumab 200 mg on Day 1. Approximately 3 weeks later, participants received carboplatin AUC 2 mg/mL/min with paclitaxel 45 mg/ m\^2 administered weekly for 6 weeks along with 2 cycles of pembrolizumab 200 mg administered every 3 weeks (Q3W) in conjunction with standard thoracic radiotherapy (TRT) (60 Gray \[Gy\] in 2 Gy fractions administered 5 days per week for 6 weeks). Participants then received 14 additional cycles of pembrolizumab 200 mg administered Q3W. 1 cycle=21 days.

Treatment:

Drug: Carboplatin AUC6

Drug: Paclitaxel 200 mg/m^2

Drug: Carboplatin AUC2

Drug: Pembrolizumab 200 mg

Drug: Paclitaxel 45 mg/m^2

Radiation: Thoracic Radiation Therapy (TRT)

Cohort B

Experimental group

Description:

Participants received 3 cycles of cisplatin 75 mg/m\^2 with pemetrexed 500 mg/m\^2 and pembrolizumab 200 mg on Day 1 of each cycle. Treatment was given in conjunction with standard TRT (60 Gy in 2 Gy fractions administered 5 days per week for 6 weeks) in cycles 2 and 3. Participants then received 14 additional cycles of pembrolizumab 200 mg administered Q3W. 1 cycle=21 days.

Treatment:

Drug: Pemetrexed 500 mg/m^2

Drug: Cisplatin 75 mg/m^2

Drug: Pembrolizumab 200 mg

Radiation: Thoracic Radiation Therapy (TRT)