Nivolumab (Opdivo) improved overall survival and was less toxic compared with docetaxel in chemotherapy-pretreated patients with nonsquamous nonâ€“small cell lung cancer.
Luis Paz-Ares, MD
Nivolumab (Opdivo) improved overall survival (OS) and was less toxic compared with docetaxel in chemotherapy-pretreated patients with nonsquamous nonsmall cell lung cancer (NSCLC), according to findings from the phase III Checkmate-057 study presented at the 2015 ASCO Annual Meeting.
“This is the first phase III study to show that immunotherapy is effective against non-squamous cell NSCLC, and appears to be particularly active in patients with PD-L1-positive tumors,” CheckMate-057 lead author Luis Paz-Ares, MD, Hospital Universitario Doce de Octubre, Madrid, Spain, said in a press conference at the ASCO meeting. “While nivolumab appears to be more potent against this most common lung cancer, it is important to note that it is also far easier on patients compared to the standard second-line treatment, docetaxel.”
In the open-label CheckMate-057, 582 patients with advanced nonsquamous NSCLC after the failure of platinum-based doublet chemotherapy were randomized to nivolumab at 3 mg/kg IV every 2 weeks (n = 292) or docetaxel at 75 mg/m2 intravenously every 3 weeks (n = 290). The treatments were administered until disease progression or unacceptable toxicity. Patients received a median of 6 and 4 doses in the nivolumab and docetaxel arms, respectively.
Patients had an ECOG performance status of 0 or 1. The median patient age was 61 years in the nivolumab arm and 64 years in the docetaxel cohort. Prior maintenance with bevacizumab, pemetrexed, or erlotinib was allowed, as was TKI therapy for known EGFR mutations or ALK translocation. Forty-percent and 38% of patients in the nivolumab and docetaxel arms, respectively, had received prior maintenance therapy. In the nivolumab arm, 15% of patients were EGFR-positive and 4% were ALK-positive, with comparable rates of 13% and 3%, respectively, in the docetaxel group.
OS was the primary endpoint, with secondary objectives focused on progression-free survival (PFS), objective response rate (ORR) per RECIST v1.1, efficacy by PD-L1 expression, and safety.
The study was stopped early after an independent monitoring panel determined the primary endpoint of improved OS had been reached. Eligible patients were allowed to continue treatment or cross over to the nivolumab arm in an open-label extension of the study.
The median OS was 12.2 months with nivolumab versus 9.4 months with docetaxel (HR = 0.73; 96% CI, 0.59-0.89;P= .00155), with a 1-year OS of 50.5% versus 39.0%, respectively.
ORR was 19% with the PD-1 inhibitor compared with 12% with chemotherapy (Odds Ratio = 1.72; 95% CI, 1.1-2.6;P= .0246). Complete and partial response rates were 1% and 18% in the nivolumab arm and <1% and 12% in the docetaxel group, respectively. The stable disease rate was 25% and 42% with PD-1 inhibition and chemotherapy, respectively.
Median time to response was 2.1 months with nivolumab versus 2.6 months with docetaxel. Median duration of response was 17.2 months versus 5.6 months in the nivolumab and control arms, respectively. Fifty-two percent of the nivolumab responses are still ongoing compared with 14% of the docetaxel responses.
Median PFS was comparable between the cohorts at 2.3 months in the nivolumab arm compared with 4.2 months in the docetaxel group (HR = 0.92; 95% CI, 0.77-1.11;P= .393). One-year PFS favored nivolumab at 18.5% versus 8.1% for the control arm.
The researchers measured PD-L1 levels in pretreatment tumor biopsies with the Dako automated IHC assay. Higher PD-L1 expression was associated with improved survival outcomes among the 78% of patients for whom PD-L1 status was detectable. “PD-L1 emerged as a clear predictive factor for the benefit from nivolumab treatment,” said Paz-Ares.
In PD-L1positive patients (PD-L1 expression on ≥1% of tumor cells), median OS was improved by 41% among 123 individuals treated with nivolumab versus 123 patients who received docetaxel (median OS = 17.2 months vs 9.0 months; HR = 0.59).
The OS benefit continued to rise as PD-L1 levels increased. The reduction in the risk of death was 57% (median OS = 18.2 months) and 60% (median OS = 19.4 months) for patients expressing PD-L1 on ≥5% and ≥10% of their tumor cells, respectively.
The researchers did not observe a similar OS benefit among patients with low or undetectable PD-L1 levels. Median OS was 10.4, 9.7, and 9.9 months among patients with PD-L1 expression levels <1%, <5%, and <10%, respectively.
Nivolumab was well tolerated and had a better safety profile than docetaxel. Among patients evaluable for safety, all-grade adverse event (AE) rates were 69% versus 88% in the nivolumab versus docetaxel arms, respectively. The most common all-grade AEs with nivolumab versus docetaxel were fatigue (16% vs 29%), nausea (12% vs 26%), decreased appetite (11 vs 16%), asthenia (10 vs 18), and diarrhea (8% vs 23%).
Grade 3-5 adverse events were reported in 10.5% of the nivolumab arm compared with 53.7% of the docetaxel cohort. The most common grade 3/4 AEs with nivolumab were fatigue, nausea, and diarrhea, at 1% each. Twenty-seven percent of patients in the docetaxel arm had grade 3/4 neutropenia versus 0 in the nivolumab arm.
Toxicity-related discontinuations occurred in 4.9% of patients receiving nivolumab compared with 14.9% of those treated with chemotherapy. Systemic therapy was administered to 42.1% and 49.7% of patients who discontinued nivolumab and docetaxel, respectively. No treatment-related deaths occurred in the nivolumab group compared with 1 in the docetaxel arm.
“The CheckMate-057 results represent progress toward establishing a new standard of care that may replace docetaxel in PD-L1 expressers,” said Paz-Ares, in a press release issued by BMS.
Nivolumab is approved by the FDA in squamous NSCLC based on data from CheckMate-017, which demonstrated an improvement in OS over docetaxel. Bristol-Myers Squibb (BMS), the manufacturer of nivolumab, has applied for an additional indication in the nonsquamous setting based on the results of Checkmate-057.
Paz-Ares LG, Horn L, Borghaei H, et al. Phase III, randomized trial (CheckMate 057) of nivolumab (NIVO) versus docetaxel (DOC) in advanced non-squamous cell (non-SQ) non-small cell lung cancer (NSCLC). J Clin Oncol. 2015;33 (suppl; abstr LBA109).