Nivolumab is the first PD-1 inhibitor to statistically significantly improve overall survival (OS) vs docetaxel in previously treated patients with advanced non-squamous cell non-small cell lung cancer (NSCLC). It significantly improved overall response rate (ORR) as well. Safety profile of nivolumab was favourable in comparison to docetaxel and consistent with prior studies. CheckMate 057 is the second randomised phase III trial to demonstrate superior survival over docetaxel in patients with advanced NSCLC. The results were reported by Dr Luis-Paz Ares on behalf of international study team at ASCO 2015 Annual Meeting (29 May – 2 June, Chicago, USA).
Options for advanced non-squamous cell NSCLC patients who progress after platinum-based doublet chemotherapy are limited, with minimal improvement in OS. Historical reports of docetaxel in second-line non-squamous cell NSCLC demonstrate median OS of 8 to 10,4 months and ORR ranged from 8,9 to 14,5%.
Nivolumab demonstrated OS benefit in patients with advanced squamous cell NSCLC in a phase III CheckMate 017 study. Based on results of that study, the US FDA on 4 March 2015 approved nivolumab as a second-line treatment for advanced squamous cell NSCLC. On 21 May 2015, the European Medicines Agency adopted a positive opinion, recommending the granting of a marketing authorisation for nivolumab, intended for the treatment of adults with locally-advanced or metastatic squamous cell NSCLC.
CheckMate 057
CheckMate 057 was a randomised, global phase III study of nivolumab, a fully human IgG4 PD-1 immune checkpoint inhibitor antibody, vs docetaxel in patients with advanced non-squamous NSCLC after failure of platinum-based doublet chemotherapy and tyrosine kinase inhibitor, if eligible.
Patients were randomised to nivolumab (n=292) or docetaxel (n=290) until progression or discontinuation due to toxicity and other reasons. The primary objective of the study was OS. Secondary objectives were investigator-assessed ORR which was measured by RECIST v1.1 criteria, progression-free survival (PFS), efficacy by PD-L1 expression, quality of life, and safety.
Nivolumab demonstrated superior OS (median OS 12,2 months in nivolumab group vs 9,4 months in docetaxel group) showing 27% reduction in risk of death (HR 0,73; p = 0.0015) and improved ORR (19.2% vs 12.4%; p = 0.0235). Median duration of response (DoR) was 17,2 months in nivolumab group vs 5,6 months in docetaxel group. HR for PFS was 0.92; p = 0.393 (median PFS 2,3 months in nivolumab group vs 4,2 months in docetaxel group.
PD-L1 expression was associated with benefit from nivolumab. In PD-L1-positive patients, nivolumab showed improved efficacy across all endpoints at predefined 1%, 5%, and 10% cut-off points. PD-L1 expression was predictive of benefit with nivolumab, starting at the lowest expression level (1%).
Median OS nearly doubled with nivolumab vs docetaxel across PD-L1 expression continuum. No difference in OS was seen when PD-L1 was not expressed in the tumour. The ORR nearly tripled in PD-L1 expressors. Median DoR was longer with nivolumab vs docetaxel in both PD-L1 expressors and non-expressors across all expression levels.
Grade 3–5 drug-related adverse events occurred in 10.5% of nivolumab and 53.7% of docetaxel patients. No deaths were related to nivolumab vs one docetaxel-related death. After discontinuation, 42.1% of nivolumab and 49.7% of docetaxel patients received subsequent systemic therapy.
Dr Ares concluded that nivolumab demonstrated superior OS vs DOC in patients with advanced non-squamous cell NSCLC after failure of platinum-based doublet chemotherapy. The safety profile of nivolumab was favorable vs docetaxel. Nivolumab demonstrated survival benefit across NSCLC histologies in two randomised phase III trials.
“Is this truly Chakemate?”
Dr Roy Herbst who discussed the study results tried to answer if the results of this study are truly “checkmate”. He said that CheckMate 057 is a practice changing and set a new standard of care in patients with previously treated non-squamous cell NSCLC. It is a positive randomised phase III study that met primary endpoint. There is a particularly long benefit in a select population of patients, even in the absence of clearly defined response. He pointed to the delayed effects of immunotherapy.
Although the biomarker data showed significant outcomes for patients expressing any level of PD-L1, PD-L1 expression was determined using archival specimens and was not available for all patients. Despite the fact that these studies are hypothesis generating, Dr Herbst commented that more work is needed before PD-L1 expression is used to determine treatment in the second-line setting and that patients were not prospectively stratified. Dr Herbst noted that the field is now grappling with multiple biomarkers associated with different immunotherapy drugs.
Nivolumab is significantly less toxic than docetaxel. Dr Herbst further noted that although positivity for the PD-L1 biomarker does improve ORR, PFS, and OS with nivolumab, even the group with less than 1% expression appeared to have at least equal activity to that of docetaxel. However, PD-L1 biomarker should not yet be used for patient selection.
Future studies are warranted to benefit a greater number of patients, in particular Dr Herbst elaborated opportunities from testing in front line therapy, as adjuvant treatment in earlier stage disease, exploring activity in patients with ALK and EGFR mutations, small-cell lung cancer, and exploring biomarkers and science to develop new combinations.
Reference
Paz-Ares L, 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 33, 2015 (suppl; abstr LBA109).