What is KEYNOTE-189? Shirish Gadgeel, MBBS of U-M Rogel Cancer Center @UMRogelCancer discusses important points to note in NSCLC.
In KEYNOTE-189, first- pembrolizumab plus pemetrexed- significantly improved overall survival (OS) and progression- survival (PFS) compared to placebo plus pemetrexed- in patients with non-- non- metastatic lung cancer (NSCLC), regardless of the expression of tumor programmed death- 1 (PD-).
Patients were allocated randomly (2:1) to receive pemetrexed and platinum plus pembrolizumab (n=410) or placebo (n=206) for 4 cycles every 3 weeks, then pemetrexed maintenance plus pembrolizumab or placebo for up to 35 cycles in total. In the placebo-combination category, eligible patients with progression of the disease may cross over to pembrolizumab monotherapy. Answer was evaluated by central analysis using RECIST (version 1.1). The revised analysis was not assigned an alpha.
About KEYNOTE - 189:
Phase III KEYNOTE-189 trial resulted in the FDA approval of the combination of pembrolizumab (Keytruda) plus chemotherapy for the treatment of non-small cell lung cancer (NSCLC) patients without EGFR or ALK alterations. Updates to the study were given at the 2019 ASCO Annual Conference, showing a longer follow-up and progression-free survival results 2 (PFS2).
Patients who obtained either pembrolizumab (n = 410) or placebo (n = 206) plus pemetrexed and carboplatin or cisplatin were randomized 2:1 in phase III trials. Patients were given 4 treatment cycles followed by pembrolizumab, or placebo was pemetrexed with maintenance. Study subjects undergoing chemotherapy were permitted to receive pembrolizumab when progressive disease developed.
The researchers obtained data and information on post-study anticancer therapy results. At the time of first-line therapy randomization, PFS2 was calculated before patients improved to their next-line medication. Approximately 45 percent of patients in the pembrolizumab plus chemotherapy arm received second-line therapy, while about 60 percent of patients received subsequent therapy in the placebo plus chemotherapy arm, including immunotherapy.
Overall, pembrolizumab plus chemotherapy provided longer OS compared to chemotherapy alone in the general population with a median OS of 22.0 months versus 10.7 months, respectively (hazard ratio [HR], 0.56; 95 per cent CI, 0.45-0.70, P < .00001) following 18.7 months of median follow-up. PFS was also substantially increased at 9.0 months versus 4.9 months compared with placebo plus chemotherapy (HR, 0.48; 95 percent CI, 0.40-0.58, P < .00001), respectively.
In patients with higher PD-L1 expression (TPS > 50 percent; n = 202), the findings showed an HR for OS of 0.59, HR for PFS of 0.36 and HR for PFS2 of 0.47; in addition, the objective response rate (ORR) was 62.1 percent for patients with high PD-L1 expression receiving pembrolizumab plus chemotherapeutic expression. The group of patients with a TPS between 1% and 49% (n = 186) showed 0.62 HR for OS, 0.51 HR for PFS, and 0.59 HR for PFS2; the ORR in this subgroup was 49.2% for added pembrolizumab, compared to 20.7% without. The group of patients with negative expression of PD-L1 (TPS < 1%; n = 190) showed 0.52 HR for OS, 0.63 HR for PFS, and 0.46 HR for PFS2; 32.3% for ORR versus 14.3% for patients undergoing combination and chemotherapy alone, respectively.
The researchers reported that pembrolizumab would improve outcomes in patients with metastatic nonsquamous NSCLC, with or without PD-L1 expression, when administered as part of first-line therapy. In addition, the investigators noticed that the mixture remained manageable with protection and tolerability, even with longer follow-up.
In an interview with Targeted Oncology, Shirish Gadgeel, MBBS of the Department of Medicine, Division of Hematology / Oncology, University of Michigan, addressed recent KEYNOTE-189 phase III research updates and possible consequences for the combination on clinical practice.