Late breaking abstracts – Checkmate 227 study

The final analyses of Checkmate 227, part 1 should help to position nivolumab + ipilimumab combination treatment ..

Written by Christine Clark

Professor Solange Peters (Lausanne, CH) updates us on data coming from the Checkmate 227 study
Professor Sanjay Popat (London, UK), Dr Thomas Newsom-Davis (London, UK) and Dr Riyaz Shah (Maidstone, UK) review the data coming from the Checkmate 227 study from a UK perspective

CheckMate 227, part 1

The Phase 3 CheckMate 227 trial compared nivolumab (nivo) + low-dose ipilimumab (ipi) against platinum doublet therapy or nivolumab / nivolumab + chemotherapy (CT) as first-line treatment in advanced, non-small cell lung cancer (NSCLC).  Ipilimumab, a CTLA-4 inhibitor, induces de novo anti-tumour T-cell responses and nivolumab (an anti-PD-1 agent restores anti-tumour T-cell function, explained Professor Solange Peters (University Hospital of Vaudois, Lausanne, Switzerland). In previous studies the ipi+nivo combination had demonstrated improved survival in renal cell carcinoma and melanoma. The ipi dosing schedule was optimised for NSCLC patients (to 1mg/kg every six weeks) to minimise toxicity.  

The final results showed that median overall survival (OS) with nivo + ipi vs CT in patients with tumour PD-L1 expression ≥ 1% was 17.1 months vs 14.9 months (hazard ratio 0.79 (95% CI 0.65 – 0.96, p= 0.007). The OS with nivo alone was 15.7 months. Patients with very high tumour PD-L1 expression (≥ 50%) had better outcomes – median OS 21.2 (95% CI 15.5-38.2), 18.1 (95% CI 14.4-22.1) and 14.0 (95% CI 10.0-18.6) for nivo+ipi, nivo and CT, respectively.  Patients with tumour PD-L1 expression of less than 1% achieved a median OS of 17.2 months. In this group DoRs were 18.0 (95% CI 12.4-28.6), 8.3 (95% CI 5.9-9.4) and 4.8 (95% CI 3.7-5.8) for nivo+ipi, nivo+CT and CT.

The median OS for all randomised patients, regardless of PD-L1 status (for nivo + ipi vs CT), was 17.1 vs 13.9 months, HR 0.73 (95% CI 0.64-0.84). There was no consistent correlation between survival outcomes with nivo + ipi vs CT and PD-L1 or tumour mutational burden (TMB) alone or in combination.

The researchers concluded that dual therapy with nivo and low-dose ipi represents a potential new first-line treatment option for patients with advanced NSCLC.   

Professor Sanjay Popat (Royal Marsden, London) commented that the reported benefits may be driven by patients with high PD-L1 tumour expression. Nivo monotherapy had no role in the front- line setting due to its limited efficacy, he continued, and ipi adds efficacy but at “a meaningful cost of toxicity”. Based on these results, nivo + ipi could be a treatment option if tumour PD-L1 expression is less than 1% or if it is above 50% but cannot be recommended for 1-49%.

He also noted that the high rate of adverse events (AEs) – 33% grade 3-4 with combination treatment and 12% discontinuation rate – was higher than for CT or nivo alone.

Pembrolizumab is the standard to beat in this situation, he said but, as for nivo + ipi, “Caveat emptor!” was his advice.   

Based on presentations given at the European Society for Medical Oncology Congress, Barcelona, September 2019