First-Line Nivolumab in Stage IV or Recurrent NSCLC with a PD-L1 Expression Level of 5% or More

In CheckMate 026, nivolumab was not associated with longer PFS than chemotherapy

In CheckMate 026 study, nivolumab was not associated with significantly longer progression-free survival (PFS) than chemotherapy among patients with previously untreated stage IV or recurrent non–small cell lung cancer (NSCLC) with a PD-L1 expression level of 5% or more. The overall survival (OS) was similar between the groups. Nivolumab had a favourable safety profile, as compared with chemotherapy, with no new or unexpected safety signals, the study investigators reported in 22 June 2017 issue of The New England Journal of Medicine (NEJM).

In a background, the authors explained that in two phase III trials, nivolumab resulted in significantly longer OS than docetaxel among patients with metastatic NSCLC who had disease progression during or after platinum-based chemotherapy. Benefit was seen regardless of the PD-L1 expression level but was enhanced in patients with non-squamous NSCLC with increased PD-L1 expression.

In an international, randomised, open-label phase III trial, CheckMate 026 (ClinicalTrials.gov number, NCT02041533) the study investigators compared first-line nivolumab with chemotherapy in patients with PD-L1–positive NSCLC.

In the NEJM paper, they reported the efficacy and safety of nivolumab compared to platinum-based chemotherapy as first-line therapy in patients with stage IV or recurrent NSCLC with a PD-L1 expression level of 5% or more (primary efficacy analysis population) and those with a PD-L1 expression level of 1% or more (secondary efficacy analysis population). Furthermore, they reported an exploratory analysis to assess the effects of the tumour-mutation burden on treatment outcomes.

The study investigators assigned, in a 1:1 ratio, patients to receive nivolumab (administered intravenously at a dose of 3 mg per kilogram of body weight once every 2 weeks) or platinum-based chemotherapy (administered once every 3 weeks for up to six cycles). Patients receiving chemotherapy could cross over to receive nivolumab at the time of disease progression.

The primary endpoint was PFS, as assessed by blinded independent central review, among patients with a PD-L1 expression level of 5% or more.

Of 1325 patients enrolled in the trial, 541 (41%) underwent randomisation, with 271 assigned to receive nivolumab and 270 assigned to receive chemotherapy. A total of 784 patients (59%) did not undergo randomisation because their PD-L1 samples could not be evaluated, because the PD-L1 expression level was less than 1%, or because they did not meet other trial criteria. During screening, 71% of patients who had PD-L1 results that could be evaluated had a PD-L1 expression of 1% or more. Overall, 530 patients (98% of all the patients who had undergone randomisation) received treatment.

Among the 423 patients with a PD-L1 expression level of 5% or more, the median PFS was 4.2 months with nivolumab versus 5.9 months with chemotherapy (hazard ratio [HR] for disease progression or death, 1.15; 95% confidence interval [CI], 0.91 to 1.45; p = 0.25), and the median OS was 14.4 months versus 13.2 months (HR for death, 1.02; 95% CI, 0.80 to 1.30).

An exploratory analysis was conducted in 312 patients (58% of the patients who had undergone randomisation) to assess the effect of the tumour-mutation burden on outcomes. The percentage of patients with a high tumour-mutation burden was imbalanced between the treatment groups (30% in the nivolumab group vs. 39% in the chemotherapy group).

Among the patients with a high tumour-mutation burden, the response rate was higher in the nivolumab group than in the chemotherapy group (47% vs. 28%), and PFS was longer (median, 9.7 vs. 5.8 months; hazard ratio for disease progression or death, 0.62; 95% CI, 0.38 to 1.00). The OS was similar between groups regardless of the tumour-mutation burden. However, 68% of the patients with a high tumour-mutation burden in the chemotherapy group received subsequent nivolumab because of treatment crossover, access to nivolumab after the trial, or both. There was no significant association between tumour-mutation burden and PD-L1 expression level. However, in the nivolumab group, patients with both a high tumour-mutation burden and a PD-L1 expression level of 50% or more had a higher response rate (75%) than those with only one of these factors (32% among patients with a high tumour-mutation burden only and 34% among those with a PD-L1 expression level of ≥50% only) or neither factor (16%). However, this comparison was not powered for statistical analysis.

In term of findings related to high tumour-mutation observations, the authors wrote that it was an exploratory analysis that was not prespecified, the data are hypothesis-generating and require further prospective validation.

Treatment crossover

A total of 128 of 212 patients (60%) in the chemotherapy group received nivolumab as subsequent therapy.

The authors commented that “given that nivolumab therapy prolongs survival among previously treated patients with advanced NSCLC, the high frequency of subsequent nivolumab treatment may have contributed to the favorable overall survival in the chemotherapy group. In addition, imbalances in the characteristics of the patients at baseline may have favored the chemotherapy group, including disease characteristics that are associated with a better prognosis (i.e., slightly fewer liver metastases, smaller tumor burden, and a higher proportion of women). Two factors that appear in retrospect to have had an influence on the response to nivolumab (i.e., a PD-L1 expression level of ≥50% and a high tumor-mutation burden) also disfavored the nivolumab group, which had lower proportions of such patients than did the chemotherapy group.

Two additional observations worth noting are the high percentage of patients in this trial who had received radiotherapy previously (39%) and the median time from diagnosis to randomization of approximately 2 months.”

Side effects

Treatment-related adverse events of any grade occurred in 71% of the patients who received nivolumab and in 92% of those who received chemotherapy. Treatment-related adverse events of grade 3 or 4 occurred in 18% of the patients who received nivolumab and in 51% of those who received chemotherapy.

Differences between CheckMate 026 and KEYNOTE-024

The KEYNOTE-024 trial established a role for pembrolizumab as first-line treatment in patients with NSCLC with a PD-L1 expression level of 50% or more as determined by the Dako 22C3 PD-L1 test in a prospectively designed trial. The median PFS was 10.3 months in the pembrolizumab group and 6.0 months in the chemotherapy group. The response rate was 45% in the pembrolizumab group and 28% in the chemotherapy group.

Analyses comparing treatment efficacy in patients with a PD-L1 expression level of 50% or more were not prespecified in CheckMate 026. Other differences between these two trials include different assays to assess PD-L1 tumour expression, the criteria related to previous radiotherapy and glucocorticoid use during the trials, and imbalances between groups in the characteristics of the patients (e.g., sex in CheckMate 026 and the lower percentage of patients who had never smoked in the immunotherapy group in KEYNOTE-024 [3%] than in CheckMate 026 [11%]).

The CheckMate 026 was supported by Bristol-Myers Squibb, ONO Pharmaceutical, a Cancer Center Support Grant (CA016672, to MD Anderson Cancer Center [Dr Blumenschein]) from the US National Institutes of Health, and a Hollings Cancer Center K12 Paul Calabresi Career Development Grant (K12 CA157688, to Dr Wrangle). The study team thank the staff of Dako for collaborative development of the PD-L1 IHC 28-8 pharmDx assay.