Pembrolizumab-chemo combo improves survival in metastatic NSCLC
The addition of pembrolizumab to a pemetrexed-platinum chemotherapy regimen improved overall survival (OS) and progression-free survival (PFS) in patients with advanced non-squamous non-small-cell lung cancer (NSCLC), findings from the phase III KEYNOTE-189* trial show.
“Results from KEYNOTE-189 are practice-changing,” said study lead author Associate Professor Leena Gandhi from the Perlmutter Cancer Center at NYU Langone Health, New York City, New York, US. “This phase III trial demonstrated an improvement in overall response rate, PFS, and OS across all groups of patients, irrespective of PD-L1 expression, halving the risk of death, which is an unprecedented effect of therapy in the first-line setting for advanced non-squamous NSCLC without EGFR or ALK alterations,” she said.
Participants were 616 treatment-naïve adults with metastatic non-squamous NSCLC without sensitizing ALK or EGFR mutations receiving pemetrexed (500 mg/m2) and a platinum-based treatment (cisplatin [75 mg/m2] or carboplatin [AUC 5 mg/mL/min]) who were randomized to receive either pembrolizumab (200 mg; n=410, median age 65 years, 62 percent male) or placebo (n=206, median age 63.5 years, 52.9 percent male) intravenously every 3 weeks for four cycles. This was followed by either pembrolizumab or placebo for up to 35 cycles plus pemetrexed maintenance therapy.
Patients were followed up for a median 10.5 months, with a mean 7.4 and 5.4 months treatment duration for patients in the pembrolizumab and placebo groups, respectively. Sixty-seven patients assigned to placebo crossed over to receive pembrolizumab following disease progression, while 18 received anti-PD-L1 therapy outside the study.
Superior efficacy with pembrolizumab
Twelve-month estimated OS rate was superior among patients on pembrolizumab-chemotherapy compared with placebo-chemotherapy (69.2 percent vs 49.4 percent; median, not reached vs 11.3 months, hazard ratio [HR], 0.49, 95 percent confidence interval [CI], 0.38–0.64; p<0.001). [AACR 2018, presentation CT075; N Engl J Med 2018;doi:10.1056/NEJMoa1801005]
OS benefit with pembrolizumab was evident regardless of PD-L1 status with HRs of 0.59, 0.55, and 0.42 for patients with PD-L1 tumour proportion scores of <1 percent, 1–49 percent, and ≥50 percent, respectively.
PFS was also greater among patients on pembrolizumab-chemotherapy compared with placebo-chemotherapy (34.1 percent vs 17.3 percent; median, 8.8 vs 4.9 months, HR, 0.52, 95 percent CI, 0.43–0.64; p<0.001).
Compared with patients on placebo-chemotherapy, patients on pembrolizumab-chemotherapy also showed better tumour response rate (47.6 percent vs 18.9 percent), disease control rate (84.6 percent vs 70.4 percent), and median response duration (11.2 months vs 7.8 months).
Grade ≥3 adverse events (AEs) occurred in 67.2 and 65.8 percent of patients on pembrolizumab-chemotherapy and placebo-chemotherapy, respectively, with anaemia (16.3 percent vs 15.3 percent) and neutropenia (15.8 percent vs 11.9 percent) the most frequently reported (≥10 percent of patients). Acute kidney injury (AKI) occurred more frequently among patients on pembrolizumab-chemotherapy compared with placebo-chemotherapy (5.2 percent vs 0.5 percent), as did immune-mediated AEs (22.7 percent vs 11.9 percent).
Treatment discontinuation due to AEs occurred in 13.8 and 7.9 percent of patients on pembrolizumab-chemotherapy and placebo-chemotherapy, respectively, with a 20.2 and 10.4 percent discontinuation rate specifically for pembrolizumab and placebo, respectively. AE-related deaths occurred in 6.7 and 5.9 percent of patients on pembrolizumab-chemotherapy and placebo-chemotherapy, respectively.
Upfront PD-1 inhibition preferred?
According to the researchers, while PD-1 inhibitors such as pembrolizumab have been approved as second-line treatment for metastatic NSCLC, few patients receive second-line therapy due to the rapid disease progression in advanced NSCLC. [Front Med (Lausanne) 2017;4:4; PLoS One 2017;12:e0175679]
“The long-term survival of patients with advanced NSCLC remains poor and the standard of care for most patients is chemotherapy, which affords a survival benefit measured in months,” said Gandhi.
“Despite a 50 percent crossover rate [in this trial], there was still a very clear survival benefit, suggesting that combination therapy upfront may be better than if PD-1/PD-L1 inhibitors are given later in the course of illness,” she said.
Future research will have to assess if pembrolizumab monotherapy would suffice in this group of patients or whether a pembrolizumab-pemetrexed-platinum chemotherapy regimen would be more efficacious, said the researchers.