Pembrolizumab, Pemetrexed, and Platinum Chemotherapy Combination Shows Improved OS and PFS in Patients with Metastatic Nonsquamous NSCLC

The results from an interim analysis of the pivotal, randomized, double-blind, phase 3 KEYNOTE-189 trial comparing the efficacy and safety of platinum-doublet chemotherapy with and without pembrolizumab (Keytruda) for the first-line treatment of patients with metastatic, nonsquamous non–small-cell lung cancer (NSCLC) met the study’s primary outcome measures of progression-free survival (PFS) and overall survival (OS).¹ Treatment with the regimen led to significantly longer PFS and OS than pemetrexed plus platinum chemotherapy alone in this patient population, regardless of PD-L1 expression.¹

Pembrolizumab is a humanized monoclonal antibody that binds to the PD-1 receptor and blocks the immune-suppressing ligands, PD-L1 and PD-L2, from interacting with PD-1 to aid in restoring T-cell and immune responses.² Approved by the FDA in several cancer types, pembrolizumab received accelerated approval in May 2017 for the first-line treatment of patients with metastatic, nonsquamous NSCLC, based on tumor response rate and PFS.³ Results from this interim analysis, conducted by the independent Data Monitoring Committee, will be submitted to regulatory authorities for review, and will be presented at an upcoming medical meeting.¹

“This approval marks an important milestone in the treatment of lung cancer. Now, pembrolizumab in combination with pemetrexed and carboplatin can be prescribed in the first-line setting for patients with metastatic nonsquamous non–small cell lung cancer, irrespective of PD-L1 expression,” said Corey Langer, MD, Director of Thoracic Oncology and Professor of Medicine, Hospital of the University of Pennsylvania, Philadelphia.³

For the study, investigators enrolled 614 patients aged ≥18 years without EGFR or ALK mutations, with Eastern Cooperative Oncology Group performance status 0 to 1, and who had not received systemic therapy for advanced disease.^1,4 Patients were randomized 2:1 to receive 200 mg pembrolizumab plus 500 mg/m² pemetrexed with vitamin supplementation plus 75 mg/m² cisplatin or carboplatin AUC 5 on day 1 every 3 weeks (Q3W) for 4 cycles, followed by 200 mg pembrolizumab plus 500 mg/m² pemetrexed Q3W; or placebo plus 500 mg/m² pemetrexed with vitamin supplementation plus 75 mg/m² cisplatin or carboplatin AUC 5 on day 1 Q3W for 4 cycles, followed by placebo plus 500 mg/m² pemetrexed Q3W until disease progression.^1,4,5 Patients receiving placebo who had disease progression verified by central independent review could undergo unblinding to their treatment assignment and receive open-label pembrolizumab.¹ All drugs were administered via intravenous infusion.⁵

The primary outcome measures of PFS (measured by Response Evaluation Criteria in Solid Tumors [RECIST] 1.1 as assessed by blinded central imaging) and OS, were both evaluated for a time frame of up to 24 months.⁵ The study’s secondary outcome measures were overall response rate per RECIST 1.1 as assessed by blinded central imaging for a time frame of up to 24 months, duration of response per RECIST 1.1 as assessed by blinded central imaging for a time frame of up to 24 months, number of patients who experienced an adverse event (AE), evaluated for a time frame of up to 27 months, and number of patients who discontinued study treatment due to an AE, measured for a time frame of up to 24 months.⁵

In the study regimen, pembrolizumab demonstrated a safety profile consistent with that previously observed.¹

References
1. Merck’s KEYTRUDA® (pembrolizumab) significantly improved overall survival and progression-free survival as first-line treatment in combination with pemetrexed and platinum chemotherapy for patients with metastatic nonsquamous non-small cell lung cancer (KEYNOTE-189). January 16, 2018. www.businesswire.com/news/home/20180116005680/en/Mercks-KEYTRUDA-pembrolizumab-Significantly-Improved-Survival-Progression-Free. Accessed January 23, 2018.
2. Merck. Mechanism of action of KEYTRUDA® (pembrolizumab). www.keytruda.com/hcp/mechanism-of-action/. Accessed January 24, 2018.
3. ASCO Post. FDA approves pembrolizumab as first-line combination therapy with pemetrexed and carboplatin for metastatic nonsquamous NSCLC. May 11, 2017. www.ascopost.com/News/55616. Accessed January 24, 2017.
4. Hall RD, Gadgeel SM, Garon EB, et al. Phase 3 study of platinum-based chemotherapy with or without pembrolizumab for first-line metastatic, nonsquamous non-small cell lung carcinoma (NSCLC): KEYNOTE-189. J Clin Oncol. 34:15 Suppl. DOI: 10.1200/JCO.2016.34.15_suppl.TPS9104. Epub before print.
5. Clinicaltrials.gov. Study of Pemetrexed+Platinum Chemotherapy With or Without Pembrolizumab (MK-3475) in Participants With First Line Metastatic Nonsquamous Non-small Cell Lung Cancer (MK-3475-189/KEYNOTE-189). Updated December 1, 2017. www.clinicaltrials.gov/ct2/show/NCT02578680?term=NCT02578680&rank=1. Accessed January 22, 2018.