CHICAGO-For patients having advanced non-small cell lung cancer (NSCLC) without any targetable mutations, the first-line therapy is platinum-based chemotherapy. For those patients having tumor proportion scores of 50 percent or greater for PD-L1, cytotoxic chemotherapy has very recently been replaced by the anti-PD-1 antibody pembrolizumab as the first-line treatment of choice. However, a majority of NSCLC patients have a tumor proportion score of less than 50 percent.
To compare the use of platinum-based cytotoxic chemotherapy with or without pembrolizumab in patients with metastatic NSCLC, irrespective of their tumor PD-L1 expression levels, the phase III KEYNOTE-189 trial was initiated. Recently, data from the first interim analysis of this trial were reported at the 2018 AACR Annual Meeting by Leena Gandhi, MD, PhD, Associate Professor of Medicine and Director of Thoracic Medical Oncology Program, Perlmutter Cancer Center at NYU Langone Health. Concurrent to that presentation was the publication of these results in the New England Journal of Medicine (2018; doi:10.1056/NEJMoa1801005).
"Results from KEYNOTE-189 are practice-changing; this phase III trial demonstrated an improvement in overall response rate, progression-free survival (PFS), and overall survival (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 nonsquamous NSCLC without EGFR or ALK alterations," Gandhi noted.
Background
"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," Gandhi stated. "Unfortunately, patients with advanced NSCLC can often undergo rapid clinical deterioration during disease progression and, consequently, less than one half of patients with advanced NSCLC ever receive second-line therapy (for which the current standard is immunotherapy)."
The randomized phase II KEYNOTE-021 trial, which evaluated the use of carboplatin plus pemetrexed with or without pembrolizumab, showed significantly improved rates of response and longer PFS for participants receiving pembrolizumab plus chemotherapy over those treated with chemotherapy alone (Lancet Oncol 2016;17:1497-1508). In May 2017, the use of pembrolizumab plus pemetrexed and carboplatin-based chemotherapy was approved by the FDA as a first-line treatment for patients with advanced non-squamous NSCLC.
"This approval was largely based on data from the phase II cohort G of the KEYNOTE-021 study, but it was not widely adopted in the absence of positive results from a phase III study," Gandhi explained. "Further, the phase II study did not initially demonstrate a survival benefit."
When explaining the rationale for combined therapy utilized in this study, Gandhi noted, "Modulation of the immune response through PD-1 inhibition may be enhanced by the potential immunogenic effects of cytotoxic chemotherapy, such as increasing the potential for antigen cross-presentation by dendritic cells after the destruction of tumor cells, inhibiting myeloid-derived suppressor cells, increasing the ratio of cytotoxic lymphocytes to regulatory T cells, and blocking the STAT6 pathway to enhance dendritic cell activity."
Methodology
Participation in this study was limited to those meeting the following criteria:
* 18 years of age or more;
* pathologically confirmed metastatic nonsquamous NSCLC;
* no sensitizing EGFR or ALK mutations;
* no previous systemic therapy for metastatic disease;
* an ECOG performance status score of 0 or 1;
* at least one measurable lesion according to RECIST v.1.19 criteria; and
* a tumor sample provided for determination of PD-L1 expression levels.
Among the following were key exclusion criteria:
* a history of noninfectious pneumonitis that required glucocorticoid use;
* an active autoimmune disease;
* receiving systemic immunosuppressive therapy; and
* receiving more than 30 Gy of radiotherapy to the lung in the previous 6 months (because of increased risk of pneumonitis).
Regarding central nervous system metastases in patients, Gandhi noted, "These were not a cause for exclusion unless they were large (> 1.5 cm) or required treatment (and then participation was allowed after treatment). Asymptomatic lesions up to 1.5 cm (up to three lesions) were allowed without prior treatment; others had to have prior radiation treatment before enrollment."
Patients were randomized in a 2:1 ratio to receive either 200 mg of pembrolizumab (pembrolizumab combination group) or saline placebo (placebo combination group) IV Q3W for up to 35 cycles. Additionally, all participants received four cycles of the investigator's choice of cisplatin (75 mg/m2) or carboplatin (AUC 5 mg/mL/min) plus pemetrexed (500 mg/m2), all IV Q3W, followed by pemetrexed (500 mg/m2) Q3W. Participants in both study groups also received premedication with folic acid, vitamin B12, and glucocorticoids in accordance with local guidelines for pemetrexed use. Patients in the placebo-combination group who had verified disease progression were permitted to crossover to pembrolizumab monotherapy.
The two primary endpoints were OS, defined as the time from randomization to death from any cause, and PFS, the time between randomization and death from any cause or blinded, independent central radiologic review-assessed disease progression, whichever occurred first. Secondary endpoints included response rate (the percentage of patients with a confirmed complete or partial response); duration of response (DOR) (time from first documented complete response or partial response to disease progression or death); and safety. Both the response rate and the DOR were assessed by blinded, independent central radiologic review. Exploratory endpoints included patient-reported outcomes and the effect of PD-L1 expression on efficacy.
Study Results
A total of 965 patients were screened at 126 sites in 16 countries and, of these, a total of 616 met all eligibility criteria and were enrolled between February 2016 and March 2017. These participants were randomized to either the pembrolizumab combination group (410 patients) or the placebo combination group (206 patients). Baseline demographic and disease characteristics were generally considered to be well balanced between the groups, although, there was a higher percentage of men in the pembrolizumab combination group (62.0%) than in the placebo combination group (52.9%) (p=0.04). A PD-L1 tumor proportion score of >=1 percent was noted for 63.0 percent of the patients, 72.2 percent of the patients utilized carboplatin as the platinum-based drug, while 88.1 percent of the patients were current or former smokers.
There were 235 deaths in the intention-to-treat population, while the estimated proportion of patients alive at 12 months was 69.2 percent (95% CI: 64.1-73.8%) in the pembrolizumab combination group and 49.4 percent (95% CI: 42.1-56.2%) in the placebo combination group. The median OS was not reached in the pembrolizumab combination group and was 11.3 months (95% CI: 8.7-15.1 months) for the placebo combination group, affording a hazard ratio (HR) for death of 0.49 (95% CI: 0.38-0.64; p<0.001).
"The benefit of the pembrolizumab combination was observed in all PD-L1 tumor proportion score subgroups that were analyzed: < 1 percent (12-month OS rate-61.7% vs. 52.2%; HR for death-0.59; 95% CI: 0.38-0.92); 1-49 percent (12-month OS rate-71.5% vs. 50.9%; HR-0.55; 95% CI: 0.34-0.90); >=50 percent (12-month OS rate-73.0% vs. 48.1%; HR-0.42; 95% CI: 0.26-0.68)," Gandhi stated.
With 410 events of progression or death, the median PFS was 8.8 months (95% CI: 7.6-9.2 months) and 4.9 months (95% CI: 4.7-5.5 months) in the pembrolizumab-combination and placebo-combination groups, respectively, giving an HR for progression or death of 0.52 (95% CI: 0.43-0.64; p<0.001). The estimated proportion of patients alive and progression-free at 12 months was 34.1 percent (95% CI: 28.8-39.5%) in the pembrolizumab-combination group and 17.3 percent (95% CI: 12.0-23.5%) in the placebo-combination group.
"The hazard ratio for progression-free survival was less than 1.00 across all analyzed subgroups and across all PD-L1 tumor proportion score subgroups, although the upper boundaries of the 95 percent CIs crossed 1.00 for patients 65 years or older (median: 9.0 vs. 6.7 months; HR: 0.75; 95% CI: 0.55-1.02) and those with PD-L1 tumor proportion scores of < 1 percent (median: 6.1 vs. 5.1 months; HR: 0.75; 95% CI: 0.53-1.05)," Gandhi explained.
The response rate assessed by blinded, independent central radiologic review was 47.6 percent (95% CI: 42.6-52.5%) and 18.9 percent (95% CI: 13.8:25.0%) in the pembrolizumab-combination group and placebo-combination group, respectively (p<0.001).
The median DOR was 11.2 months (range, 1.1+ to 18.0+) and 7.8 months (range, 2.1+ to 16.4+) in the pembrolizumab-combination and placebo-combination groups, respectively. In the preceding, the use of the plus signs in the ranges indicates there was no progressive disease at the time of the last disease assessment. Across all categories of PD-L1 tumor proportion scores, the response rate was higher in the pembrolizumab-combination group than in the placebo-combination group; the greatest between-group difference was noted in those patients having tumor proportion scores of >=50 percent (61.4% vs. 22.9%).
Discussion
"Despite a 50 percent crossover rate, 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," Gandhi said. "Together with the results from KEYNOTE-024, the data from KEYNOTE-189 suggest that introducing immunotherapy as a first-line therapy may have a favorable long-term effect on outcomes.
"A limitation of the study is that it was not designed to assess whether those with high PD-L1 expression benefited from pembrolizumab alone versus pembrolizumab plus chemotherapy," Gandhi noted. "The placebo combination arm did not perform as well as some historical controls, but this was a rigorous randomized study which did show a clear difference between the two arms," she said.
"The survival benefit associated with the pembrolizumab combination was observed in all subgroups of PD-L1 tumor proportion scores, including patients with a score of less than 1 percent, a population for which single-agent PD-1 and PD-L1 inhibition have a small chance of benefit," Gandhi explained. "The greatest relative benefit was observed in patients having PD-L1 tumor proportion scores of >=50 percent, a finding that was consistent with the results of previous PD-1 pathway inhibition studies in advanced NSCLC."
Concerning possible future investigations, Gandhi commented, "An important question for further study is whether the addition of pembrolizumab to pemetrexed and a platinum-based drug has greater efficacy than pembrolizumab monotherapy in these patients; without direct comparisons, it will be necessary for physicians and patients to have individualized discussions of benefit."
Richard Simoneaux is a contributing writer.