Suresh Ramalingam on Remaining Questions With Checkpoint Inhibitors in NSCLC

Suresh S. Ramalingam, MD

Checkpoint inhibitors are quickly gaining traction as a leading therapeutic option in advanced lung cancer.

In October 2015, the FDA granted an accelerated approval to pembrolizumab (Keytruda) for patients with advanced non—small cell lung cancer (NSCLC) whose disease had progressed after other treatments and with tumors that express PD-L1.

At about the same time, the FDA expanded its approval of nivolumab (Opdivo) to include patients with nonsquamous NSCLC who progressed on or following platinum-based chemotherapy, EGFR-, or ALK-targeted agents in patients harboring those mutations. Nivolumab was initially approved in March 2015 for patients with advanced squamous NSCLC following progression on platinum-based chemotherapy.

Both of these agents are currently being investigated in numerous combinations, including with CTLA-4 and IDO inhibitors.

Additional checkpoint inhibitors are also showing promise. Atezolizumab (MPDL3280A) doubled overall survival compared with docetaxel in previously treated patients with PD-L1—positive squamous NSCLC. The anti–PD-L1 agent has also been shown to improve survival in combination with chemotherapy.

OncLive: What are the biggest questions that remain regarding the use of immunotherapy in lung cancer?

To learn more about the evolving role of checkpoint inhibitors in lung cancer and what challenges still remain, OncLive spoke with Suresh Ramalingam, MD, professor, Emory School of Medicine, and chief, Medical Oncology, Department of Hematology and Medical Oncology, Emory University. Ramalingam: Immunotherapy is now for real in lung cancer. We have two approved drugs in the form of pembrolizumab and nivolumab for advanced-stage NSCLC. Therefore, the key question now is, “How do we build on the benefits of these agents? Is it through combinations? Is it through novel ways to enhance the efficacy of these agents to try and use them in different settings of lung cancer? Can we transfer what is a palliative benefit into a curative benefit?” These are all important questions to answer.

What do you see on the horizon for the use of immunotherapy in lung cancer?

We now have a better understanding of what is required for a patient’s immune system to attack their tumor. Mutation burden seems to be one of the most important things. The higher the mutation burden, the more likely the immune checkpoint inhibitors are able to work. The question then is, “Can we, based on an increased understanding of various steps that have to be working in consort with immune checkpoint recognition, translate what we know into a therapeutic benefit?” Right now, one area of focus is sequencing immune checkpoint inhibitors with chemotherapy. There are also promising combination approaches out there. There is the possibility of combining immune checkpoint inhibitors with other steps in the immune recognition and immune attack cascade.

Are there specific combinations you see potential for with checkpoint inhibitors?

In other words, there is the possibility of targeting other immune stimulating molecules in conjunction with immune checkpoint inhibitors. We are also seeing the emergence of a new class of agents that can be given in combination with immune checkpoint inhibitors, such as the IDO inhibitors. There are a number of exciting developments and, as a result of this, we are going to see checkpoint inhibitors move from second-line therapy for NSCLC to potentially earlier stages within the treatment of metastatic disease, and perhaps even earlier stages than that. We are investigating if we can block both PD-1 and CTLA-4 in a concurrent manner to attempt to maximize the immune attack in the activated T cells in the tumor. We are seeing early results where the response rates seem to be higher in NSCLC and, even in small cell lung cancer, we see that the combination is showing promise. That provides us the proof of principle to go after other such combination approaches. We also know that you can combine these agents with chemotherapy. As we understand specifically how various chemotherapy agents affect different steps in the immune pathways, we may be able to identify certain pathways that are more conducive to immune checkpoint inhibitors.

There are trials that are looking at the combination of checkpoint inhibitors with various combination chemotherapy agents. One example is atezolizumab in combination with chemotherapy. Atezolizumab is a PD-L1 targeted monoclonal antibody and it has already shown activity as a single agent in NSCLC. Recently, there were early data in the frontline setting for patients with previously untreated advanced stage disease for atezolizumab combined with chemotherapy. Investigators reported high response rates, a high degree of disease control, and potentially durable benefits for these patients who respond. This has formed the basis for phase III trials that are designed to give either chemotherapy alone or with atezolizumab in patients with advanced NSCLC.

The third broad approach I see on the horizon is using checkpoint inhibitors with radiation. We know that when a tumor is radiated, there is a release of tumor antigens. Can we capitalize on that by bringing in a checkpoint inhibitor to improve the benefits?

These are some of the ways that people are already thinking about combining these agents, and I am sure this is going to expand as we develop new agents. The main goal is to individualize these agents to specific patients based on biomarkers in their tumors or other factors. That is obviously an important area of research, as well.