ESMO 2016

Pembrolizumab 'should be first line treatment' for high PD1 expressing NSCLC patients

Dr Martin Reck - Lung Clinic Grosshansdorf, Grosshansdorf, Germany

The background is the fact that platinum-based chemotherapy is the current standard of care in patients with advanced non-small cell lung cancer without any targetable oncogenic alterations. On the other hand, we have seen that pembrolizumab, an anti-PD1 antibody, which is approved in Europe for pre-treated patients with advanced PD-L1 positive non-small cell lung cancer has shown substantial efficacy in combination with a good safety profile in pre-treated patients as well as in treatment naïve patients with advanced non-small cell lung cancer. Furthermore, we have seen a strong correlation of the efficacy of pembrolizumab with the PD-L1 expression on the tumour and this has led to the concept of the KEYNOTE-024 trial.

This has been the design of KEYNOTE-24: 305 untreated patients with advanced non-small cell lung cancer were randomised either to standard of care which consisted of platinum-based chemotherapy or pembrolizumab given at a dose of 200mg every three weeks until disease progression. In the group of patients randomised to the chemotherapy arm at progression there was the opportunity to cross over to pembrolizumab.

Patients without activating EGF receptor mutations or ALK translocation without untreated brain metastases or active autoimmune diseases were illegible for the trial when a high PD-L1 expression status has been confirmed centrally. The key primary endpoint of KEYNOTE-024 has been progression free survival assessed by independent central radiological review. Secondary endpoints consisted of overall survival, response and safety.

The primary endpoint has been progression free survival and we have seen a significant improvement in progression free survival favouring treatment with pembrolizumab corresponding to a prolongation of the median progression free survival from 6 up to 10.3 months corresponding to a hazard ratio of 0.5 and corresponding to a p-value of below 0.001. This benefit has been consistent and improving over time with a six month progression free survival rate of 50% compared to 62% and a one year progression free survival rate of 15% compared to 48% in favour of pembrolizumab.

Overall survival also has been analysed and has been significantly improved in favour of treatment with pembrolizumab corresponding to a hazard ratio of 0.6, corresponding to a p-value of 0.005. Similar to progression free survival, the benefit in overall survival has been consistent and improving over time with a six month overall survival rate of 72% compared to 80% and a one year overall survival rate of 54% compared to 70%. This improvement and overall survival has been observed despite a crossover rate of roughly 50% to anti-PD1 agents. Therefore this trial has been stopped based on the recommendations of the DMC.

Time on treatment has been longer for pembrolizumab, with a median time on treatment of 3.5 months compared to 7 months. Tolerability also has been in favour of pembrolizumab with a lower number of treatment related adverse events. Predominantly when we look on the number of clinically relevant treatment related adverse events, the grade 3 and 4 adverse events, where we did see an incidence rate of 26% compared to 51%.

So, in summary, KEYNOTE-024 has been a positive trial. We have seen a significant improvement in progression free survival for pembrolizumab compared to chemotherapy in untreated patients with advanced high PD-L1 expressing non-small cell lung cancer corresponding to a hazard ratio of 0.5. We have seen a significant improvement in overall survival corresponding to a hazard ratio of 0.6, despite a crossover of 50%. We have seen a favourable tolerability profile and looking on the tolerability profile of pembrolizumab this has been exactly in the range of side effects that we have seen in previous pembrolizumab trials.

So for this group of patients, untreated patients with advanced non-small cell lung cancer with a high PD-L1 expression this treatment option is quite favourable for further treatment approaches. Thank you.