In a phase III trial the immunotherapy nivolumab (Opdivo) improved overall survival and was less toxic than docetaxel in both nonsquamous and squamous nonâ€“small cell lung cancer.
Luis Paz-Ares, MD
In a phase III trial the immunotherapy nivolumab (Opdivo) improved overall survival and was less toxic than docetaxel in nonsquamous non—small cell lung cancer (NSCLC).
The PD-L1 inhibitor was approved by the FDA for squamous NSCLC based on findings of the CheckMate-017 trial. The drug’s manufacturer, Bristol-Myers Squibb, has applied for an additional indication in the nonsquamous setting, based on these CheckMate-057 results reported at the 2015 ASCO Annual Meeting by lead author Luis Paz-Ares, MD, of the Hospital Universitario Doce de Octubre in Madrid, Spain:
“Nivolumab is the first PD-1 inhibitor to significantly improve overall survival as compared to docetaxel in [NSCLC] patients with prior treatment and nonsquamous histology,” he said.
The results showing efficacy and safety in nonsquamous NSCLC are notable in part because NSCLC accounts for 85% of all lung cancers, and more than two-thirds of the cases are nonsquamous, ASCO noted in a statement.
“Even five years ago, an effective immunotherapy for lung cancer was largely considered impossible,” noted ASCO expert Gregory A. Masters, MD, FACP, FASCO, who moderated the press briefing where the CheckMate-057 results were announced. “Today, we have such a treatment, and it surpasses the standard treatment in terms of efficacy and patient quality of life.”
The open-label CheckMate-057 trial randomized 582 patients with advanced nonsquamous NSCLC after the failure of platinum-based doublet chemotherapy 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. ALK- and EGFR-positivity were comparable in both arms.
Overall survival (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.
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.
Positive Results on Secondary Endpoints
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.
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-L1—positive 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.
“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 statement.
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).