Firstline pembrolizumab plus chemo improves NSCLC outcomes
Dr Corey Langer - University of Pennsylvania, Philadelphia, USA
By way of background, patients with non-small cell who do not demonstrate actionable markers, either EGFR mutation or ALK or ROS1 translocations, are generally treated with first line platinum-based combination chemotherapy. As we’ve heard from Dr Reck, pembrolizumab, an anti-PD1 monoclonal antibody, that has shown activity as single agent in patients with advanced pre-treated non-small cell and it’s approved in the EU for treating patients with advanced PD-L1 expressing non-small cell that has progressed on one or more prior chemotherapy regimens. So adding pembro to chemotherapy may improve efficacy because the therapies have complementary mechanisms of action and generally non-overlapping toxicities.
Our study scheme is shown here. Key eligibility criteria included treatment naïve advanced stage 3b or 4 non-squamous non-small cell lung cancer; absence of activating EGFR mutation or ALK translocation; good performance status, no active CNS metastases; no antecedent interstitial lung disease or pneumonitis requiring systemic steroids and provision of a tissue sample adequate for PD-L1 assessment. Patients were randomised and stratified for, but not selected by, PD-L1 status and the results of that PD-L1 status were blinded to the individual investigators.
The control arm featured carboplatin at AEC of 5 with pemetrexed 500mg/m2 every three weeks for four cycles. The investigational arm added pembrolizumab to that regimen at a flat dose of 200mg every three weeks for up to two years. Both arms featured maintenance therapy with pemetrexed single agent indefinitely. The control arm was allowed to crossover to single agent pembrolizumab at the time of disease progression.
The primary endpoint was overall response rate, as evaluated by a blinded independent central review. The key secondary endpoint was progression free survival and the other secondary endpoints included overall survival, safety and relationship between PD-L1 status and anti-tumour activity.
After 10.6 months follow-up 47% remain on pembrolizumab, 31% are still receiving chemotherapy and 51% in the chemo arm have received subsequent pembro or other checkpoint inhibitors, this is for the control group. The results are shown here – on the left we have response rate that is superior for the combination, 55% for combined pembrolizumab and chemotherapy compared to 29% for chemotherapy alone, this was highly significant. Progression free survival is also significantly improved for the combination with a hazard ratio of 0.53 and a p-value of 0.0102. At six months 77% are free from progression in the pembro combination compared to 63% in the control group and the median progression free survival for the pembro chemo combination is over a year, it’s 13 months compared to 8.9 months for chemotherapy alone. Again the p-value for the response benefit is 0.0016.
If we look at time on treatment a median of 8 months for the pembro-chemo combo compared to 4.9 months for chemotherapy alone. We do see a higher incidence of grade 3 and 4 toxicity at 39% for the pembro combination compared to 26% for chemotherapy alone but this does not translate into any difference in treatment discontinuation or deaths on study, as shown here. Side effect profile is basically as expected that you would see with pembrolizumab and platinum-based combinations, no major surprises.
So, in summary, adding pembrolizumab to standard carboplatin pemetrexed in non-squamous non-small cell nearly doubles the chance of having a response to treatment and reduces the risk of progression or death by nearly 50% over standard chemotherapy alone, carbo and pemetrexed. Pembrolizumab in combination with carboplatin and pemetrexed is tolerable, has a readily manageable side effect profile and this combination could eventually be an effective treatment option for patients with chemotherapy naïve advanced non-squamous non-small cell. There is an ongoing prospective randomised phase III trial, 189, that is essentially the phase III version of what I’ve just presented with PFS as the primary endpoint including crossover in the control arm. The results of this trial have just been published in Lancet Oncology, I don’t know if we have handouts for that but it will be available in the Exhibit Hall when that opens, the Lancet Oncology booth.