Corey Langer, MD
The treatment landscape for patients with non-small cell lung cancer (NSCLC) is poised to undergo dramatic changes, as novel immunotherapies, second-generation targeted therapies, and new maintenance strategies continue to show promise in clinical trials.
As these multiple advances move forward, there remain several unanswered questions. Historically, immunotherapeutic approaches have not been effective in lung cancer. However, early-phase results for antibodies against the immune checkpoints programmed death-1 (PD-1) and its ligand (PD-L1) have sparked great enthusiasm in the lung cancer community. Additionally, as multiple next-generation ALK and EGFR inhibitors progress rapidly toward approval, it remains unclear where they will fit with current treatments, and whether there is an optimal sequence for patients with NSCLC.
To explore these conundrums, Corey J. Langer, MD, led a recent OncLive
Peer Exchange® roundtable discussion entitled “Improving Clinical Outcomes in NSCLC.” This discussion explored frontline treatment approaches and evolving maintenance strategies for patients with advanced NSCLC.
Immune Checkpoint Inhibition
A variety of therapies are in development in lung cancer that target immune checkpoints. As a result of the efficacy seen with these agents, checkpoint inhibitors are being explored across a number of settings for patients with NSCLC, including in earlier stage, locally advanced NSCLC and in the adjuvant setting.
“I think this class of drugs has generated considerable enthusiasm within the thoracic community, for good reason,” said Benjamin P. Levy, MD. “I think, historically speaking, immunotherapeutic approaches in lung cancer have failed, and this class of drugs has ushered in a new era, working by suppressing inhibitory signaling in the immune system, basically uncamouflaging the tumor cell and allowing the T cells to recognize it.”Targeting PD-1
Results for the anti-PD-1 inhibitor nivolumab in heavily pretreated patients with NSCLC were presented at the World Conference on Lung Cancer in October 2013.1
This trial enrolled 129 patients with NSCLC and demonstrated an overall response rate (ORR) of 17%, with a greater than 18-month median duration of response (DOR). The median overall survival (OS) for all dosages and histologies was 9.6 months. At the 3-mg/kg dosage that will be explored in phase III trials, the median OS increased to 14.9 months.
In general, the toxicity profile for nivolumab was manageable, with less than 5% of patients experiencing adverse events of grade 3/4 severity. However, these agents still do have toxicity, the panelists cautioned, but overall they are very well tolerated.
In addition to nivolumab, the PD-1 immune checkpoint inhibitor MK-3475 also demonstrated activity in highly pretreated patients with NSCLC.2
In this investigation, the ORR was 21% by RECIST criteria with an initial immune-related response of 24%. The DOR with MK-3475 was durable, although not yet reached in the analysis.Targeting PD-L1
A similar approach to targeting PD-1 directly targets the associated ligand, PD-L1. The lead treatment in this space, MPDL3280A, currently has less data than the PD-1 inhibitors but seems to have similar efficacy and safety. In data presented at the World Conference on Lung Cancer, the ORR with MPDL3280A was 23%.3
PDL1 inhibition appeared effective, regardless of smoking status, KRAS status, or the number of prior therapies received. The only significant indicator of response in this study was PD-L1 status.
Corey J. Langer, MD
Director of Thoracic Oncology
University of Pennsylvania Abramson Cancer Center
Mark G. Kris, MD
Professor of Thoracic Oncology
Memorial Sloan Kettering Cancer Center
New York, NY
Benjamin P. Levy, MD
Director of Thoracic Medical Oncology
Mount Sinai Beth Israel
New York, NY
Mark A. Socinski, MD
Professor of Medicine
University of Pittsburgh
Heather A. Wakelee, MD
Associate Professor of Medicine (Oncology)
Stanford University School of Medicine
Given these findings, the lead biomarker under exploration for the immune checkpoint inhibitors is PD-L1. At this point, separate assays are being utilized along with each agent, making cross comparison between studies difficult.