Treatment of non-small-cell lung cancer (NSCLC) remains a challenge. After failure of first-line chemotherapy, benefit from second-line treatment is slim. At present, docetaxel, pemetrexed and erlotinib are approved second-line options, with an average response rate of 8-9% and median overall survival (OS) of 8 months1. Two recently reported trials showed that adding ramucirumab or nintedanib to docetaxel, modestly improves OS over docetaxel alone 2-3. A number of clinical trials are evaluating the efficacy and safety of immune checkpoint inhibitors such as anti PD1/PD-L1 antibodies, for the treatment of NSCLC.
Nivolumab is a fully human IgG4 anti PD-1 antibody. Recently, the results of two phase III trials comparing docetaxel with nivolumab in pretreated advanced squamous and non-squamous NSCLC (CheckMate 017 and CheckMate 057) have been reported 4,5. In both studies, treatment was continued until progressive disease, intolerable toxicity or withdrawal of consent.
In CheckMate 017, 272 patients with squamous histology were randomised to receive nivolumab at the dose of 3 mg/kg every 2 weeks, or docetaxel 75 mg/m2 every 3 weeks. Median OS (primary endpoint) was 9.2 months for the nivolumab group and 6 months for the chemotherapy arm (HR of 0.59% (CI:95% CI, 0.44 to 0.79; P<0.001). The objective response rate (ORR) was 20% vs 9% for nivolumab and docetaxel, respectively (p = 0.008). Median progression-free survival (PFS) (3.5 vs. 2.8 months, HR 0.62; 95% CI, 0.47 to 0.81; p<0.001) and 1-year survival rate (42% vs 24%) were also improved in the nivolumab arm. In this trial, 83% of overall population was evaluable for PD-L1 expression (archival and recent tumour sample). Across the pre-specified expression levels (≥1%, ≥5% and ≥10%), PD-L1 expression was not prognostic or predictive of any of the efficacy endpoints.
CheckMate 057 was recently presented at the ASCO annual meeting. This study randomized 582 pretreated patients with non-squamous NSCLC to receive nivolumab (n=292) or docetaxel (n= 290). The study showed an improvement in ORR (19.2% vs. 12.4%) and OS (12.2 vs. 9.4 months, HR 0.73, CI: 0.59-0.89; p=0.0015) in the nivolumab arm but no difference in PFS (2.3 vs. 4.2 months, HR 95%, CI:95%, 0.77-1-11, p=03932). Duration of response was significantly longer in the nivolumab arm (17.1 months vs. 5.6 months). In this trial, 78% of randomized population had a quantifiable PD-L1 expression. For patients with PD-L1+ tumours treated with nivolumab, there was an increment in ORR and OS for all three cut-off points whilst for PD-L1- patients there was no difference in OS. It is important to point out that these analyses are mostly from archival tumor samples and, as PD-L1 expression can change after exposure to chemotherapy, EGFR-TKis or radiotherapy, it is difficult to draw firm conclusions on the predictive value of this biomarker in this pre-treated population.
In both studies, the safety profile of nivolumab was more favorable than docetaxel. Less than 10% of patients receiving nivolumab developed immune-mediated adverse events. These adverse events were infrequent and usually of low grade; the rate of grade 3-4 pneumonitis was 1% in both studies.
The results of these two randomised trials confirm nivolumab to be superior to docetaxel in the second-line setting for squamous and non-squamous NSCLC and establish a new standard of care.
- Should we consider nivolumab for all non-squamous patients with NSCLC progressing after a first-line platinum based therapy or should the drug be given only to PD-L1 positive patients?
- The trials allowed patients to be treated until progressive disease. Would a shorter treatment with nivolumab be equally effective?
1. Weiss JM and Stinchcombe TE. Second-Line Therapy for Advanced NSCLC. Oncologist. 2013;18(8):947-53.
2. Garon EB, Ciuleanu TE, Arrieta O, et al. Ramucirumab plus docetaxel versus placebo plus docetaxel for second-line treatment of stage IV non-small-cell lung cancer after disease progression on platinum-based therapy (REVEL): a multicentre, double-blind, randomised phase 3 trial. Lancet. 2014 Aug 23;384(9944):665-73
3. Reck M, Kaiser R, Mellemgaard A, et al. Docetaxel plus nintedanib versus docetaxel plus placebo in patients with previously treated non-small-cell lung cancer (LUME-Lung 1): a phase 3, double-blind, randomised controlled trial. Lancet Oncol. 2014 Feb;15(2):143-55.
4. Brahmer J, Reckamp KL, Baas P, et al. Nivolumab versus Docetaxel in Advanced Squamous-Cell Non-Small-Cell Lung Cancer. N Engl J Med. 2015 May 31. [Epub ahead of print]
5. 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)
Dr Califano has received honoraria from Bristol Myers Squibb. Dr Passaro declares no conflict of interests.
The content of this article reflects the personal opinion of the author and is not necessarily the official position of the European Society for Medical Oncology.