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Nivolumab plus chemotherapy as first-line therapy showed improved progression-free survival compared to chemotherapy in NSCLC patients with less than 1% PD-L1 expression

CheckMate 227 is a phase III multi-part study investigating first-line nivolumab-based therapy versus chemotherapy in advanced non-small cell lung cancer (NSCLC). Previously it was shown that the trial met its primary endpoint by demonstrating an improved progression-free survival (PFS) with the nivolumab-ipilimumab combination compared to chemotherapy in the subgroup of patients with a tumour mutation burden (TMB) of at least 10 mut/Mb. During ASCO 2018, updated results were shown of the comparison of nivolumab plus chemotherapy versus chemotherapy alone in patients with very low levels of PD-L1 expression (<1%).

In the PD-L1 low part of the Checkmate 227 trial, 550 patients with chemotherapy-naïve, stage IV/recurrent NSCLC without known sensitizing EGFR/ALK mutations and a tumour PD-L1 expression of less than 1% were randomized (1:1:1) to receive either nivolumab (3mg/kg q2w) + ipilimumab (1mg/kg q6w), nivolumab (360mg q3w) + chemotherapy, or chemotherapy alone (of note pemetrexed maintenance after chemotherapy for non-squamous patients was allowed). Patients in the study were treated for up to 2 years.

The baseline disease and patients characteristics were well-balanced between nivolumab + chemotherapy (N=177) and chemotherapy alone (N=186) arms. After a minimum follow-up of 11.2 months, the PFS was shown to be significantly longer with nivolumab-chemotherapy than with chemotherapy alone (median PFS: 5.6 versus 4.7months; HR[95%CI]: 0.74[0.58-0.94]). At the 1-year landmark, 26% of the nivolumab-chemotherapy treated patients were free of progression as compared to 14% in the chemotherapy arm. Also with respect to objective response rate (36.7% versus 23.1%) and duration of response (median 7.2 versus 4.7 months), the nivolumab-chemotherapy combination outperformed chemotherapy alone. The benefit of nivolumab-chemotherapy over chemotherapy alone was seen in all investigated subgroups, irrespective of age, sex, geographical region and ECOG performance status. Looking at the PFS data in function of the TMB the investigators showed a clear PFS benefit with the nivolumab-chemotherapy combination in patients with TMB ≥10 mut/Mb and tumour PD-L1 expression <1% (HR[95%CI]: 0.56[0.35-0.91]; 1year PFS rate 27% versus 8%). In contrast, patients with PD-L1 <1% and a TMB <10 mut/Mb did not seem to benefit from the addition of nivolumab to chemotherapy (HR[95%CI]: 0.87[0.57-1.33]; 1 year PFS rate 18% versus 16%). Among histologic subgroups, the benefit of nivolumab-chemotherapy was more pronounced in non-squamous (HR: 0.68) relative to squamous NSCLC patients (HR: 0.92).

Checkmate 227 also allows comparing nivolumab-ipilimumab with nivolumab-chemotherapy. In the subgroup of patients with PD-L1<1% and a TMB ≥10 mut/Mb, the median PFS was 6.2 months with chemotherapy-nivolumab and 7.7 months with nivolumab-ipilimumab, both significantly longer than the 5.3 months seen with chemotherapy alone (HR 0.56 and 0.48, respectively). At 1 year this is translated into a PFS rate of 8% with chemotherapy, 27% with chemotherapy-nivolumab and 45% with nivolumab-ipilimumab. Importantly, the duration of response in this subgroup was particularly pronounced with nivolumab-ipilimumab, with 93% of these patients having a response of 1 year or longer (versus 33% with nivolumab-chemotherapy. No responses beyond 1 year on chemotherapy). Also when considering nivolumab-ipilimumab in the TMB <10 mut/Mb and PD-L1 <1% subgroup it appeared that these patients don’t seem to benefit from immune checkpoint inhibition (1 year PFS rate 18%, similar to other 2 arms).

The incidence of grade 3/4 treatment-related adverse events was 52% with the nivolumab-chemotherapy combination as compared to 25% with the nivolumab-ipilimumab combination and 35% with chemotherapy alone. The rate of treatment discontinuation due to adverse events was similar in all 3 arms (13% with nivolumab-chemotherapy, 16% with nivolumab-ipilimumab and 14% with chemotherapy).

In summary, first-line nivolumab + chemotherapy improved the PFS compared to chemotherapy in patients with advanced NSCLC and <1% tumour PD-L1 expression. This benefit was driven by patients with a PD-L1 expression <1% and a TMB ≥10 mut/Mb. Patients with low PD-L1 expression and a low TMB (<10 mut/Mb) did not seem to benefit from nivolumab either in combination with chemotherapy, or ipilimumab. Responses were more durable and 1-year PFS rates were higher with nivolumab-ipilimumab than with nivolumab-chemotherapy in patients with a high TMB and <1% PD-L1 expression.


Borghaei H, et al. Nivolumab (Nivo) + platinum-doublet chemotherapy (Chemo) vs chemo as first-line (1L) treatment (Tx) for advanced non-small cell lung cancer (NSCLC) with <1% tumor PD-L1 expression: Results from CheckMate 227. Presented at ASCO 2018; Abstract 9001.

Speaker Hossein Borgheai


Hossein Borgheai, MD, PhD, Fox Chase Cancer Center, Philadelphia, PA, USA


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