Karen Kelly, MD
Following the demonstration of success as single-agents, a number of clinical trials are now assessing PD-1 and PD-L1 inhibitors in combination with chemotherapy, targeted therapies, and radiation therapy in an attempt to further improve outcomes for patients with non–small cell lung cancer (NSCLC), according to presentations at the 2015 International Lung Cancer Congress.
At this time, investigations into combinations of checkpoint inhibitors with targeted therapies or radiation are largely in their nascence, with an extensive demonstration of efficacy still pending. However, early findings for chemotherapy with PD-1/PD-L1 inhibitors have shown promising signs of clinical efficacy and tolerability, resulting in the initiation of several phase III investigations.
"Ideally, we want these agents to cause immunogenic cell death," Karen Kelly, MD, associate director for clinical research at the UC Davis Comprehensive Cancer Center, said at the meeting. "This is defined as a form of regulated cell death that is capable of activating an adaptive immune response, and importantly inducing immunologic memory. It relies on the release of endogenous danger signals from dying cells. Several chemotherapeutics can elicit this type of cell death."
PD-1/PD-L1 With Chemotherapy
In the phase I CheckMate-012 study, nivolumab with platinum-based doublet chemotherapy demonstrated signs of efficacy as a frontline treatment for patients with NSCLC.1
This study explored a number of chemotherapy doublets, including gemcitabine and cisplatin (gem/cis), pemetrexed and cisplatin (pem/cis), and paclitaxel and carboplatin (pac/carbo).
In patients treated with the 10-mg/kg dose of nivolumab, the objective response rate (ORR) was 33% with gem/cis (n = 12) and 47% each with pem/cis (n = 15) and pac/carbo (n = 15). For nivolumab at 5 mg/kg in combination with pac/carbo (n = 14), the ORR was 43%.
The 18-month overall survival (OS) rates were 33%, 60%, and 40% in the 10-mg/kg arm for gem/cis, pem/cis, and pac/carbo, respectively. The median OS was 51, 83, and 65 weeks, for gem/cis, pem/cis, and pac/carbo, respectively. In the pac/carbo plus nivolumab at 5-mg/kg arm, the OS rate was 86%. The median OS was not yet reached in this arm.
"My impression of this data is really that if there's a signal here, it's a very faint signal, at least for nivolumab in this combination," Kelly said.
In addition to data for nivolumab, findings presented at the 2015 ASCO Annual Meeting showed a reasonable safety profile and antitumor activity with the frontline combination of pembrolizumab and platinum-based doublet chemotherapy.2
In this study, patients received pembrolizumab for up to 2 years at 10 mg/kg or 2 mg/kg in combination with 4 cycles of pac/carbo or pemetrexed plus carboplatin (pem/carbo). The ORR in those who received pac/carbo was 28%, across both doses of pembrolizumab. At the 2 mg/kg (n = 13) and 10 mg/kg (n = 12) doses, the ORR was 38% and 17%, respectively.
In the pem/carbo arm, the ORR across both doses was 58%. The best response was seen with the 10-mg/kg dose of pembrolizumab (n = 12), with an ORR of 75% and a disease control rate (DCR) of 100%. In the 2-mg/kg arm (n = 12), the ORR was 42% and the DCR was 100%.
"With paclitaxel and carboplatin it really was not impressive. However, when we look at the pem/carboplatin, the response rate was a little more impressive," Kelly said. "There could perhaps be a hint of activity here with pem/carboplatin in this early phase I trial in a highly selected group of patients."
Pembrolizumab combination strategies continue to be explored in the phase II KEYNOTE-021. This study will combine pembrolizumab at various doses with chemotherapy doublets. Additionally, the study will assess the PD-1 inhibitor along with bevacizumab, gefitinib, erlotinib, and ipilimumab for applicable patients (NCT02039674).
In addition to PD-1 inhibitors, the PD-L1 agent atezolizumab has shown promising efficacy in a phase Ib study for patients with chemotherapy-naive advanced NSCLC.3
Across all arms the ORR was 67% with the combination of atezolizumab and chemotherapy. The ORR was 60% with pac/carbo (n = 8), 75% with pem/carbo (n = 14), and 62% with nab-paclitaxel plus carboplatin (n = 15). In the nab-paclitaxel arm, 2 patients experienced a complete response.
"I get more optimistic when I see data like this, but I do want to remind everyone that these are going to be highly selected patients and the numbers are small," Kelly said.