November 2019

By Tom Newsom-Davis, BTOG Vice-Chair

1st Line Combination Immunotherapy for NSCLC: Checkmate-227

Further results from the Checkmate-227 trial were presented at ESMO 2019. Checkmate-227 is a study with multiple treatment arms, which has released results at various stages since 2018. It has also undergone amendments along the way, influenced by other trial results. Interpretation is therefore complex and the audience was aided at ESMO 2019 by the discussion ed by Sanjay Popat (Chairman of the BTOG Steering Committee).

The Study
Checkmate-227 is a large study involving over 1,500 patients with treatment naïve NSCLC, according to PD-L1 status. In essence it is comparing chemotherapy with the combination of the anti-PD-1 agent nivolumab (3mg/kg) and the anti-CTLA-4 agent ipilimumab (1mg/kg). In some arms, the combination of chemotherapy and nivolumab is also a comparator, and in others single-agent nivolumab was used.

Results and Interpretation
At ESMO 2019, two main results were presented. The first was overall survival (OS) data from patients with PD-L1 1% NSCLC treated with either chemotherapy, nivolumab or combination nivolumab+ipilimumab. The median OS was 14.9, 15.7 and 17.1 months respectively, and 2-year OS was 33%, 36% and 40%.

Although on the face of it this would seem to suggest that nivolumab+ipilimumab is the preferred option in this patient group, there are a number of reasons why this is not the case. Firstly, the benefit of this combination over chemotherapy was modest (hazard ratio 0.79). Secondly, the benefit seems to be predominantly driven by the sub-set of patients with PD-L1 >50%. Thirdly, combination chemotherapy and immunotherapy is now seen as standard of care in PD-L1 1% NSCLC and so comparing nivolumab and ipilimumab to chemotherapy alone is less relevant.

Previous data from Checkmate-227 had suggested that the combination of nivolumab+ipilimumab might be especially effective in patients whose tumours had high tumour mutation burden (TMB). However the results presented at ESMO 2019 found no difference in overall survival in TMB-high (>10mut/Mb) or low (<10mut/Mb) patients.

The other data presented involved patients with PD-L1 negative tumours (<1%) and compared chemotherapy, chemotherapy plus nivolumab, and nivolumab+ipilimumab. Median OS was 12.2, 15.2 and 17.2 months respectively. This means that combination nivolumab and ipilimumab are a treatment option in PD-L1 negative NSCLC.

Combination nivolumab-ipilimumab is not without its issues, and one focus was side effects: 33% of patients reported grade 3-4 adverse events, and a 12% discontinued treatment as a result of side effects. These rates are almost double those of nivolumab alone.

Conclusions
Professor Popat drew the following conclusions in the discussion session:
1. Nivolumab monotherapy has no role in the 1st line treatment of NSCLC
2. Nivolumab-Ipilimumab is a first line option for PD-L1 <1% NSCLC, but it does not seem to be better than existing chemo-immunotherapy combinations, and may be more toxic
3. Nivolumab-Ipilimumab is not better than existing chemo-immunotherapy in PD-L1 1-49% NSCLC and so is not recommended
4. Nivolumab-Ipilimumab is an option for PD-L1 >50% NSCLC, but caution is needed because excess patients seem to die early during treatment
5. Tumour mutational burden (TMB) does not help us decide whether to use nivolumab-ipilimumab or not

Nivolumab+Ipilimumab are not currently licensed for the treatment of NSCLC, and this regimen has yet to be assessed by NICE.

Link to Checkmate-227 New England Journal of Medicine publication